Antimicrobial compositions containing colloids of oligodynamic metals

ABSTRACT

The present invention relates to antimicrobial compositions, methods for the production of these compositions, and use of these compositions with medical devices, such as catheters, and implants. The compositions of the present invention advantageously provide varying release kinetics for the active ions in the compositions due to the different water solubilities of the ions, allowing antimicrobial release profiles to be tailored for a given application and providing for sustained antimicrobial activity over time. More particularly, the invention relates to polymer compositions containing colloids comprised of salts of one or more oligodynamic metal, such as silver. The process of the invention includes mixing a solution of one or more oligodynamic metal salts with a polymer solution or dispersion and precipitating a colloid of the salts by addition of other salts to the solution which react with some or all of the first metal salts. The compositions can be incorporated into articles or can be employed as a coating on articles such as medical devices. Coatings may be on all or part of a surface.

PRIOR RELATED APPLICATIONS

[0001] This application is a continuation-in-part application of U.S.patent application Ser. No. 09/461,846, filed Dec. 15, 1999. Thisapplication also claims the benefit of U.S. provisional patentapplication serial No. 60/405,936, filed Aug. 26, 2003, U.S. provisionalpatent application serial No. 60/406,343, filed Aug. 26, 2002, U.S.provisional patent application serial No. 60/406,384, filed Aug. 26,2002, U.S. provisional patent application serial No. 60/406,496, filedAug. 28, 2002, and U.S. provisional patent application serial No.60/406,497, filed Aug. 28, 2002.

FIELD OF THE INVENTION

[0002] The present invention relates generally to polymer compositionsand their use for making or coating articles, such as medical devices.More specifically the invention relates to antimicrobial compositionscontaining a polymer and oligodynamic salts. Further, the presentinvention relates to compositions containing active agents as well asoligodynamic salts and their use.

BACKGROUND OF THE INVENTION

[0003] For many years silver and silver salts have been used asantimicrobial agents. An early medicinal use of silver was theapplication of aqueous silver nitrate solutions to prevent eye infectionin newborn babies. Silver salts, colloids, and complexes have also beenused to prevent and to control infection. For example, colloidalmetallic silver has been used topically for conjunctivitis, urethritis,and vaginitis.

[0004] Other metals, such as gold, zinc, copper, and cerium, have alsobeen found to possess antimicrobial properties, both alone and incombination with silver. These and other metals have been shown toprovide antimicrobial behavior even in minute quantities, a propertyreferred to as “oligodynamic.”

[0005] Additionally, silver is known for antimicrobial use with medicaldevices, such as catheters, cannulae, and stents. One conventionalapproach for obtaining antimicrobial medical devices is the depositionof metallic silver directly onto the surface of the substrate, forexample, by vapor coating, sputter coating, or ion beam coating.However, these noncontact deposition coating techniques suffer manydrawbacks. These drawbacks include poor adhesion, lack of coatinguniformity, and the need for special processing conditions, such aspreparation in darkness due to the light sensitivity of some silversalts. One particular drawback of these coatings is that the processesby which the coatings are formed do not adequately coat hidden orenclosed areas, such as the interior lumen of a catheter or stent.Additionally, these methods produce coatings that are very much likemetallic silver in that they do not release silver from the coating andrequire contact with the coating to provide antimicrobial action. Thoughhigh concentrations of silver may be deposited on the substrate, verylittle free ionic silver is released on exposure to aqueous fluid. As aresult, these coatings provide only limited antimicrobial activity. Theyessentially retard colonization of microbial agents on the surface ofthe device. However, because they do not release sufficient silver ionsinto aqueous fluids, they offer little or no protection from bacteriacarried into the body upon insertion of the device and do not inhibitinfection in the surrounding tissue.

[0006] Another method of coating silver onto a substrate involvesdeposition or electrodeposition of silver from solution. Drawbacks ofthese methods include poor adhesion, low silver pick-up on thesubstrate, the need for surface preparation, and high labor costsassociated with multistep dipping operations usually required to producethe coatings. Adhesion problems have been addressed by inclusion ofdeposition agents and stabilizing agents, such as gold and platinummetals, or by forming chemical complexes between a silver compound andthe substrate surface. However, inclusion of additional componentsincreases the complexity and cost of producing such coatings.

[0007] With many medical devices, it is preferred to have a lubriciouscoating on the device. Lubricious coatings aid device insertion, reducethe trauma to tissue, and reduce the adherence of bacteria. Anotherdrawback to conventional methods which apply silver and other metalsdirectly onto the surface of a medical device for which a lubriciouscoating is also desired is that a second, lubricious coating must beapplied to the device over the antimicrobial coating, adding tomanufacturing cost and time.

[0008] Some of these coatings release, to varying degrees, silver ionsinto the solution or tissue surrounding the substrate. However,activation of such coatings often requires conditions that are notsuitable for use with medical implants, such as catheters, stents, andcannulae. These conditions include abrasion of the coating surface,heating to a temperature above 180° C., contact with hydrogen peroxide,and treatment with an electric current.

[0009] Another conventional approach for obtaining antimicrobial medicaldevices is the incorporation of silver, silver salts, and otherantimicrobial compounds into the polymeric substrate material from whichthe article is formed. An oligodynamic metal may be physicallyincorporated into the polymeric substrate in a variety of ways. Forexample, a liquid solution of a silver salt may be dipped, sprayed orbrushed onto the solid polymer, for example, in pellet form, prior toformation of the polymeric article. Alternatively, a solid form of thesilver salt can be mixed with a finely divided or liquefied polymericresin, which is then molded into the article. Further, the oligodynamiccompound can be mixed with monomers of the material prior topolymerization.

[0010] There are several disadvantages to this approach. One suchdisadvantage is that larger quantities of the oligodynamic material arerequired to provide effective antimicrobial activity at the surface ofthe device. A second disadvantage is that it is difficult to producearticles that allow for the release of the oligodynamic material becausemost device polymers absorb little, if any, water to aid in thediffusion and release of the oligodynamic material, resulting inarticles that provide only a limited antimicrobial effect.

[0011] Yet another approach for obtaining antimicrobial medical devicesis the incorporation of oligodynamic agents into a polymeric coatingwhich is then applied to the surface of the article. Typically, anoligodynamic agent is incorporated into the coating solution in the formof a solution or a suspension of particles of the oligodynamic agent.Problems associated with this approach include poor adhesion of thecoating to the substrate, settling and agglomeration of the oligodynamicparticles, and inadequate antimicrobial activity over time.

[0012] Settling of particles of the oligodynamic agent occurs as aresult of the size and density of the particles. Settling of theparticles from such solutions can cause unpredictable changes in theconcentration of the oligodynamic agent in the composition. Thesechanges in concentration result in several drawbacks to producingcommercial products. First, unpredictable changes in the concentrationof the oligodynamic agent make it difficult to produce a compositionhaving a specific concentration of antimicrobial ions and, thus, aparticular effectiveness. Additionally, these changes make it difficultto produce multiple batches of the composition having the sameantibacterial concentration. Further, the concentration of theantimicrobial ions can affect other properties of the composition, suchas its adhesive and lubricious properties. Consistency of antimicrobialactivity is essential in the production of medical devices.

[0013] Another problem associated with particle suspensions isagglomeration of the particles. Particle agglomeration produces largerparticle sizes which increases settling of particles from solution.Additionally, the agglomeration of particles in suspensions and coatingsolutions can produce particles in the coating that are large enough tobe noticeable to the touch on the coated surface. Articles producedusing such coatings have decreased patient comfort and, therefore, areundesirable.

[0014] Many researchers have attempted to overcome these problems. Forexample, U.S. Pat. No. 4,592,920 to Murtfeldt et al. discloses a processthat attempts to overcome the settling and agglomeration problems in theart through the use of a comminuted metal having a particle size of 30microns or less. The coating of the Murtfeldt patent, however, exhibitsseveral disadvantages. For example, the Murtfeldt coating exhibits pooradhesion which is overcome by the use of the following methods. First,the Murtfeldt patent recommends pretreatment of the catheter to leachundesirable compounds that interfere with the bonding of the coating tothe surface of the catheter. Second, the Murtfeldt patent recommends theuse of a bridging compound, or primer, to attach the coating to thesurface of the catheter to increase adhesion. This adds an additionalmanufacturing step to the fabrication of a coated device. In addition tothese disadvantages, it is likely that the process used to manufactureand coat the catheters in Murtfeldt will result in settling andagglomeration problems even with the use of silver having smallerparticle sizes.

[0015] U.S. Pat. No. 4,849,223 to Pratt et al. attempts to overcomesettling and agglomeration of the particles in his invention by usingsolutions that contain high concentrations of polymer or monomer solidsand are, thus, viscous. Suspending particles in high viscosity coatingsolutions containing high polymer solids is a common method for reducingsettling and agglomeration of the particles. The coatings made by thismethod are usually very thick and, as a result, are often not uniform.Thick coatings are also more costly, dry more slowly than thin coatings,and are more difficult to manufacture. The coatings of the Pratt patentalso exhibit poor adhesion. To increase adhesion, the Pratt patentrecommends using coating materials which are similar to the substrate tobe coated, pretreating the surface of the substrate before the coatingcomposition is applied, or applying an additional coating layer betweenthe substrate and the coating.

[0016] U.S. Pat. No. 5,019,096 to Fox, Jr. et al. discloses a method forincreasing the antibacterial activity of silver by incorporating asynergistic amount of chlorhexidine and a silver salt in amatrix-forming polymer. The polymer is such that it allows for releaseof the antimicrobial agent over an extended period of time. Fox,however, relies on dispersation of silver particles into coatingsolutions and will be susceptible to problems associated with particlesettling and agglomeration.

[0017] U.S. Pat. No. 4,677,143 to Laurin et al. discloses a method toenhance release of the antimicrobial metal ions from the surface of adevice by incorporating the antimicrobial metal into a binder having alow dielectric constant that coats or forms the device. The nature ofthe binder allows the particles to form chain-like structures amongthemselves. These chain-like structures allow the surface particles todissolve to provide an initial dose of the antimicrobial agent and tocreate a pathway for interior particles to come to the surface toprovide additional doses of the antimicrobial agent over time. Laurin,however, also relies on dispersation of silver particles into coatingsolutions and is susceptible to problems associated with particlesettling and agglomeration.

[0018] U.S. Pat. No. 4,933,178 to Capelli discloses a polymer coatingcontaining an oligodynamic metal salt of a sulfonylurea. The Capellipatent attempts to improve the solubility and stability of theantimicrobial metal in the coating and to provide for the sustainedrelease of the antimicrobial agent by adding a carboxylic acid to thecoating composition. The particular carboxylic acids and the proportionsin which they are mixed determine the rate of release of theantimicrobial agent from the polymer coating composition.

[0019] U.S. Pat. No. 5,848,995 to Walder discloses the solid phaseproduction of polymers containing AgCl as an antimicrobial agent. In theWalder process, solid polymer pellets are first soaked in a solution ofsilver nitrate which is absorbed into the pellets. The pellets are thenrinsed, dried, and soaked in a solution of a sodium chloride. Thechloride ions of the salt are absorbed into the polymer matrix of thepellets where they react with the silver nitrate to form silverchloride. The pellets are then rinsed, dried, and melt processed. Thecompositions of the Walder patent are limited to hydrophilic polymers,must be thermoformed, and do not contain other silver salts to providemultiple release rates, or other oligodynamic or medicinal agents toenhance antimicrobial effectiveness.

[0020] Therefore, there is a need in the art to provide a method forrendering articles, such as medical devices, resistant to infection, onthe surface of the article, in tissue surrounding articles, or in bothlocations. There is also a need in the art for compositions which can beincorporated into articles to provide antimicrobial activity. Further,there is a need for compositions which can be employed as coatings forarticles that exhibit improved adhesion. There is also a need forcompositions that overcome the solubility, settling, and agglomerationproblems of conventional oligodynamic compositions, and exhibitenhanced, sustained release of oligodynamic agents. There is further aneed for compositions that allow delivery of one or more active agentsto locations.

SUMMARY OF THE INVENTION

[0021] Stated generally, the present invention comprises antimicrobialcompositions which in a first aspect provide the advantage of reducedsettling and agglomeration by producing a minimal particle size of theoligodynamic salts in the compositions. The use of colloids in thecompositions also permits incorporation of higher quantities ofantimicrobial ions without the difficulties associated with thesuspensions used in the prior art.

[0022] In another aspect, the compositions of the present inventionprovide the advantage of varying release kinetics for the activeoligodynamic ions due to the different water solubilities of thedifferent salts in the compositions. These varying release kineticsallow for an initial release of oligodynamic ions that providesantimicrobial activity immediately upon insertion, followed by acontinual, extended release of the oligodynamic ions from thecomposition, resulting in sustained antimicrobial activity over time.

[0023] Stated somewhat more specifically, the present invention relatesin one aspect to compositions that comprise a polymer and a colloidcontaining salts of one or more oligodynamic agents. In one disclosedembodiment, the polymer is a hydrophilic polymer. In another disclosedembodiment, the polymer is a hydrophobic polymer, while in yet anotherembodiment, the polymer is a combination of these two types of polymers.

[0024] In one disclosed embodiment, the invention comprises one or moresalts of silver as the oligodynamic agent. In another embodiment, thecomposition optionally contains additional salts of other oligodynamicmetals, such as zinc, gold, copper, cerium and the like. In yet anotherembodiment, the composition optionally comprises additional salts of oneor more noble metals to promote galvanic action. In still anotherembodiment, the composition optionally comprises additional salts ofplatinum group metals such as platinum, palladium, rhodium, iridium,ruthenium, osmium, and the like.

[0025] In a further aspect, the compositions optionally contain othercomponents that provide beneficial properties to the composition, thatimprove the antimicrobial effectiveness of the composition, or thatotherwise serve as active agents to impart additional properties to thecompositions.

[0026] In another aspect, the present invention relates to a process forproducing these antimicrobial compositions. The process comprises theformation of colloids of oligodynamic agents in solutions, dispersions,or combinations of polymers solutions and dispersions. The terms“polymer composition” and “polymer solution” are used interchangeablythroughout the specification and claims and both means any polymersolution, dispersion, or combination of polymer solutions anddispersions. The colloid can be formed first and then added to thepolymer composition or can be formed in situ in the polymer composition.Preferably, the colloid is formed in situ in the polymer composition.

[0027] The process of forming the colloids comprises, for example,combining two or more salts, wherein at least one of the salts is thesalt of an oligodynamic agent. These salts will be referred to herein assalt A and salt B. Salt A comprises one or more oligodynamic agents.Salt B comprises one or more salts that can react with salt A to form acolloid. Salts A and B can be combined in any amount and in any order.In some embodiments, it is preferred that salt A be present in astoichiometric amount or in excess when compared to salt B. In someembodiments, it is preferred that salt B be present in a stoichiometricamount or in excess when compared to salt A.

[0028] Optionally, additional components can be added to theantimicrobial compositions of the present invention. These componentsinclude, but are not limited to, additional oligodynamic agents,additional soluble salts, salts which provide galvanic action, and anyother components which provide the compositions with beneficialproperties or enhance the antimicrobial activity of the compositions.Such components include, but are not limited to, antimicrobial agents,antibiotics, and other medicinal agents.

[0029] In one disclosed embodiment, the antimicrobial composition of theinvention is produced by forming a solution, dispersion, or combinationof solutions and dispersions of one or more polymers. Next, a solutioncomprising salt A is added to the polymer composition. Then, a solutioncomprising salt B is added to the polymer composition to precipitatefine colloidal salt(s) of the oligodynamic agent(s). Where theoligodynamic agent is a metal salt, the metal cation of salt A reactswith the anion of salt B to form a less soluble salt which precipitatesas a fine colloid. Salt B is added to the polymer composition in anamount sufficient to react with some or all of salt A. Optionally, othersalts are then added in amounts to react with some or all of theremaining amount of salt A.

[0030] In another disclosed embodiment, salt B is added to the polymercomposition, followed by the addition of an excess or stoichiometricamount of salt A. In yet another embodiment, salts A and B can becombined to form a colloid which is then added to the polymercomposition.

[0031] The final polymer composition formed by these processes containsone or more colloidal salts, composed of the oligodynamic cations ofsalt A and the anions of salt B, and one or more soluble salts, composedof the anions of salt A and the cations of salt B.

[0032] The compositions are used to coat substrate materials. Thus,another aspect of the invention is a coating containing the compositionof the invention. These coatings may comprise either a single layer ormultiple layers. The compositions of the present invention are usedalone or in combination with other polymer coatings to provideadvantageous properties to the surface of the substrate. Thesecompositions are used, for example to deliver pharmaceutical agentsthat, for example, prevent infection, reduce encrustation, inhibitcoagulation, improve healing, inhibit restenosis, or impart antiviral,antifungal, antithrombogenic or other properties to coated substrates.

[0033] The compositions are also used to inhibit algae, fungal, mollusk,or microbial growth on surfaces. The compositions of the invention arealso used as herbicides, insecticides, antifogging agents, diagnosticagents, screening agents, and antifoulants.

[0034] In another aspect, the present invention relates to an article ofmanufacture which comprises the antimicrobial compositions of thepresent invention. In one embodiment, the composition is used to form anarticle or a portion of the article, for example by molding, casting,extrusion, etc. Thus, at least part of the formed article is composed ofone or more of the compositions of the present invention, alone or inadmixture with other polymeric components. In another disclosedembodiment, the composition is applied to a preformed article or part ofan article as a coating. The coated article may be produced, forexample, by dipping the article into the composition or by spraying thearticle with the composition and then drying the coated article. In apreferred embodiment, the compositions are used to coat medical devices.

[0035] It is therefore an object of the present invention to providecompositions containing a polymer and a colloid wherein the colloidcontains a salt or oxide of an oligodynamic metal.

[0036] It is another object of the present invention to providecompositions that provide antimicrobial, antibacterial, antiviral,antifungal, or antibiotic activity or some combination thereof.

[0037] It is another object of the present invention to providecompositions that, reduce encrustation, inhibit coagulation, improvehealing, inhibit restenosis, or impart antiviral, antifungal,antithrombogenic or other properties to coated substrates.

[0038] It is yet another object of the present invention to provideherbicidal or insecticidal compositions.

[0039] It is an object of the present invention to provide compositionsthat inhibit the growth of algae, mollusks, bacterial, bioslime, or somecombination thereof on surfaces.

[0040] It is a further object of the present invention to providecompositions for the delivery of active agents including, but notlimited to, pharmaceutical or therapeutic agents, growth factors,cytokines, or immunoglobulins. It is yet another object of the inventionto provide compositions that comprise a silane copolymer and abiguanide.

[0041] It is a further object of the present invention to providecompositions that comprise a silane copolymer and chlorhexidine or asalt of chlorhexidine.

[0042] It is another object of the present invention to providecompositions that comprise a silane copolymer and an antibiotic.

[0043] It is yet another object of the present invention to providetopical compositions for the delivery of pharmaceutical agents.

[0044] It is a further object of the present invention to providecompositions for the delivery of growth factors, cytokines, orimmunoglobulins.

[0045] It is a further object of the present invention to providearticles comprising the compositions of the invention including, but notlimited to articles formed in whole or in part of the compositions andarticles coated in whole or in part with the compositions.

[0046] It is a further object of the present invention to providemethods of making the compositions of the invention.

[0047] It is a further object of the present invention to providemethods of making the articles of the invention.

[0048] It is a further object of the present invention to providemethods of coating articles with the composition of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0049]FIG. 1 depicts an endotracheal tube partially coated with acoating of the present invention. Part of the tube is not coated.

[0050]FIG. 2 shows the cumulative probability of the absence ofendotracheal tube colonization with P. aeruginosa and aerobic bacteriaamong dogs receiving endotracheal tubes coated with a coating of thepresent invention and that among dogs receiving uncoated tubes. Thetubes were involved in the dog intubation study in Example 16 herein.

[0051]FIG. 3 shows box plots of tissue bacterial concentrations for allaerobic bacteria and P. aeruginosa for endotracheal tubes having acoating of the present invention and for uncoated tubes. The tubes wereinvolved in the dog intubation study in Example 16 herein. Boxesrepresent 25^(th) to 75^(th) percentiles with the 50^(th) percentile(solid line) shown within the boxes. The 10^(th) and 90^(th) percentilesare shown as capped bars.

[0052]FIG. 4 is a scatter plot of histology scores (x-axis) plottedagainst the lung tissue concentration of total aerobic bacteria(y-axis). The plotted data was generated by the dog intubation study inExample 16 herein. The regression line is shown.

[0053]FIG. 5 depicts plots of microbial adherence values of endotrachealtubes coated with a coating of the present invention and uncoatedendotracheal tubes. The raw data upon which the plots are based appearin Example 20 herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] The Composition

[0055] In a first aspect, the present invention provides antimicrobialcompositions. The compositions comprise a polymer and a colloidcomprised of the salts of one or more oligodynamic agents. The term“oligodynamic agents” as used in the present invention refers to anycompound that can provide antimicrobial activity, even when present insmall quantities.

[0056] Any polymer may be employed in the present invention, includinghydrophilic polymers, hydrophobic polymers, and mixtures of these twotypes of polymers. The use of hydrophilic polymers is preferred becausesuch polymers have additional benefits. These benefits include increasedlubricity for patient comfort, increased absorption of aqueous fluidsfrom the body which aids in the release of oligodynamic ions from thecomposition, inhibition of bacterial attachment, and improved solubilityfor some metal salts. Hydrophilic polymers best suited to the inventionare those that are soluble in water or in organic solvents containingwater. The ability to add water to the polymer composition withoutprecipitating the polymer facilitates the addition of water-solublesalts directly to the coating composition. Water facilitates theformation of salt colloids within the polymer composition. For thisreason, it is preferred that the polymer solution contain from 1 to 50%water by weight, more preferably from 5 to 30% water by weight.

[0057] However, the use of water is not limiting, as salt colloids canalso be formed using alcohols, organic solvents, or both that containlittle or no water. The use of alcohols and organic solvents, containingfrom 0 to 1% water are preferred when hydrophobic polymers are employedin the present invention.

[0058] Examples of polymers which may be used to form the compositionsinclude, but are not limited to, polyurethanes, including polyetherpolyurethanes, polyester polyurethanes, polyurethaneureas, and theircopolymers; polyvinylpyrrolidones; polyvinyl alcohols; polyethyleneglycols and their copolymers; polypropylene glycols and theircopolymers; polyoxyethylenes and their copolymers; polyacrylic acid;polyacrylamide; carboxymethyl cellulose; glycoproteins; proteoglycans;glycosaminoglycans; lipoproteins; liposaccharides; cellulose and itsderivatives; dextrans and other polysaccharides; starches; guar; xanthamand other gums and thickeners; collagen; gelatins; other naturallyoccurring polymers; polytetrafluoroethylene; polyvinyl chloride (PVC);polyvinylacetate; poly(ethylene terephthalate); silicone; polyesters;polyamides; polyureas; styrene-block copolymers; polymethylmethacrylate; acrylic-butadiene-styrene copolymers; polyethylene;polystyrene; polypropylene; natural and synthetic rubbers; acrylonitrilerubber; and mixtures and copolymers of any of the above. The preferredpolymer depends upon the substrate to be coated. In some preferred, thepolymer is a polyurethanes and polyurethane copolymers, such aspolyether polyurethaneurea. In some embodiments, hydrophobic polymersthat are chemically similar or identical to the substrate are used aloneor in combination with hydrophilic polymers to form coatings thatenhance adhesion of the coating to the substrate.

[0059] The colloid of the present invention comprises one or moreoligodynamic salts. In the discussion of the process below, theoligodynamic metal cations come from the salts referred to as salt A. Ina preferred embodiment, the oligodynamic salts comprise one or moresalts of oligodynamic metals. The salts may be different salts of thesame oligodynamic metal or may be salts of different oligodynamicmetals. Oligodynamic metals useful in the present invention include, butare not limited to, silver, platinum, gold, zinc, copper, cerium,gallium, osmium, and the like. The preferred oligodynamic metal issilver.

[0060] Salts of other metals may be employed to form the colloid. In thediscussion of the process below, these salts are referred to as salt B.These salts contain cationic ions that include, but are not limited to,calcium, sodium, lithium, aluminum, magnesium, potassium, manganese, andthe like, and may also include oligodynamic metal cations such ascopper, zinc, and the like. These salts contain anions that include, butare not limited to, acetates, acetylsalicylates, ascorbates, benzoates,bitartrates, bromides, carbonates, chlorides, citrates, folates,carbonates, deoxycholates, gluconates, iodates, iodides, lactates,laurates, oxalates, palmitates, para-aminobenzoates,para-aminosalicylates, perborates, phenosulfonates, phosphates,picrates, propionates, salicylates, stearates, succinates,sulfadiazines, sulfates, sulfides, sulfonates, tartrates, thiocyanates,thioglycolates, thiosulfates, and the like, as well as silver proteinsand silver ethylenediaminetetraacetic acid. The invention may also bepracticed with oxides serving as Salt B, including, but not limited tooxides of calcium, sodium, lithium, aluminum, magnesium, potassium,manganese, and the like, and may also include oligodynamic metal cationssuch as copper, zinc, and the like.

[0061] The compositions can contain auxiliary components. Examples ofsuch auxiliary components include, but are not limited to, viscosity andflow control agents, antioxidants, conventional pigments, air releaseagents or defoamers, and discolorants. The composition may also containconventional dyes and pigments to impart color or radiopacity or toenhance the aesthetic appearance of the compositions. The compositionscan also contain additional lubricating agents and other additives thatenhance patient comfort and tissue health.

[0062] While not wishing to be bound by the following mechanism, it isbelieved that many of the advantageous properties of some embodiments ofthe present compositions result from the differences in the solubilityof the different metal salts present in the colloid. These differingsolubilities of the metal salts in the colloid provide varying releasekinetics for the active oligodynamic metal(s). For example, with amedical device composed of, or coated with, the compositions of thepresent invention, those salts that have high water solubility will bereleased from the coating rather quickly, providing a high initial doseof antimicrobial activity to kill bacteria introduced upon insertion ofthe device in the patient. This initial dose is sometimes referred to as“quick kill,” and this antimicrobial activity is identified by theability of a coated device or composition to create zones of nobacterial growth around the device or composition when it is placed in abacterial culture. This test is known as a “zone of inhibition” assay.Those salts having lower water solubilities will be released more slowlyfrom the composition, resulting in a sustained or extended antimicrobialactivity over time.

[0063] Selection of salts having varying degrees of solubility in thecomposition allows tailoring of the composition to the specificapplication of the article comprising the composition. In oneembodiment, compositions of the invention are tailored to kill bacteriaintroduced during the insertion of a medical device, both on the surfaceof the device and in the surrounding fluid and tissue, by the quickrelease of antimicrobial metal salts, followed by prolonged inhibitionof bacterial migration and growth by the slower release of less solubleantimicrobial metal salts over an extended period of time. In anotherembodiment, the compositions contain silver salts with a very lowsolubility, thus reducing the release of silver into the fluidsurrounding the article in order to reduce tissue exposure to silverions while maintaining inhibition of microbial adherence on the surfaceof the coated article. The ability to tailor the release of theoligodynamic agent is advantageous over conventional antimicrobialcompositions, as it provides for both immediate and sustainedantimicrobial activity.

[0064] The composition may contain any amount of one or moreoligodynamic metal salts, oxides, or combination of salts and oxides. Insome embodiments, the composition contains between about 40% and about50% (based on weight of total solids in the composition) of the one ormore oligodynamic metal salts, oxides, or combination of salts andoxides. In some embodiments, the composition contains between about 30%and about 40% (based on weight of total solids in the composition) ofthe one or more oligodynamic metal salts, oxides, or combination ofsalts and oxides. In some embodiments, the composition contains betweenabout 20% and about 30% (based on weight of total solids in thecomposition) of the one or more oligodynamic metal salts, oxides, orcombination of salts and oxides. In some embodiments, the compositioncontains between about 15% and about 25% (based on weight of totalsolids in the composition) of the one or more oligodynamic metal salts,oxides, or combination of salts and oxides. In some embodiments, thecomposition contains between about 10% and about 20% (based on weight oftotal solids in the composition) of the one or more oligodynamic metalsalts, oxides, or combination of salts and oxides. In some embodiments,the composition contains between about 5% and about 15% (based on weightof total solids in the composition) of the one or more oligodynamicmetal salts, oxides, or combination of salts and oxides. In someembodiments, the composition contains between about 3% and about 8%(based on weight of total solids in the composition) of the one or moreoligodynamic metal salts, oxides, or combination of salts and oxides. Insome embodiments, the composition contains between about 4% and about 6%(based on weight of total solids in the composition) of the one or moreoligodynamic metal salts, oxides, or combination of salts and oxides. Insome embodiments, the composition contains about 5% (based on weight oftotal solids in the composition) of the one or more oligodynamic metalsalts, oxides, or combination of salts and oxides. In some embodiments,the composition contains greater than zero and up to about 5% (based onweight of total solids in the composition) of the one or moreoligodynamic metal salts, oxides, or combination of salts and oxides. Insome embodiments, the composition contains greater than zero and up toabout 2% (based on weight of total solids in the composition) of the oneor more oligodynamic metal salts, oxides, or combination of salts andoxides. In some embodiments, the composition contains between about 3%and about 4% (based on weight of total solids in the composition) of theone or more oligodynamic metal salts, oxides, or combination of saltsand oxides. In some embodiments, the composition contains about 2.5%(based on weight of total solids in the composition) of the one or moreoligodynamic metal salts, oxides, or combination of salts and oxides. Insome embodiments, the composition contains about 1% (based on weight oftotal solids in the composition) of the one or more oligodynamic metalsalts, oxides, or combination of salts and oxides.

[0065] In some embodiments, coated articles will reduce adherence of oneor more bacteria, fungi, or other microbes to the article as compared touncoated articles. In one embodiment, the coating results in an in vitrodecrease in microbial adherence of 5-95%. In another embodiment, thecoating results in a decrease in microbial adherence of at least about30%. In another embodiment, the coating results in a decrease inmicrobial adherence of at least about 50%. In another embodiment, thecoating results in a decrease in microbial adherence of at least about75%. In another embodiment, the coating results in a decrease inmicrobial adherence of at least about 90%. In another embodiment, thecoating results in a reduction of at least about 95%. Embodiments existwith any degree of reduction of adherence used. As used herein,reduction of microbial adherence is determined using the procedures setforth in EXAMPLE 18 herein.

[0066] In some embodiments, the coated articles have antimicrobialeffects upon surrounding tissues and fluids, as can be demonstratedthrough zone of inhibition testing on one or more species or strains ofbacteria, fungi, or other microorganisms. Examples of antimicrobialeffects include, but are not limited to, inhibition of growth, killing,and any other deleterious effect on microbes. In other embodiments, nozone of inhibition is created. In still other embodiments, limited zonesof inhibition are created. Embodiments also exist in which zones ofinhibition are created for some strains in a species but not others, orfor some species but not others. Embodiments also exist in which zonesof inhibition differ between microbes. As used herein, zones ofinhibition is determined using the procedures set forth in EXAMPLE 19herein. In one desirable embodiment, an article is coated with acomposition comprising colloidal silver chloride. The resulting articlereduces or eliminates adherence of microbes on the surface of theendotracheal tube but releases silver to surrounding tissues at such aslow rate due to the low solubility of silver chloride that the articledoes not produce zones in the zone of inhibition assay.

[0067] By tailoring the release profile of the oligodynamic metals, itis possible to develop any article having any combination ofantimicrobial effects on the surface and surrounding tissues and fluids.Thus, any of the above combinations of effects are achieved. Forexample, in some embodiments microbial adherence of a specific speciesor strain of organisms is reduced (including any of the % reductionsnoted above) while these embodiments produce little or no zone ofinhibition for the same species or strain. Embodiments also exist inwhich both zone of inhibition and microbial adherence differ betweenorganisms.

[0068] In some embodiments, the use of the coatings reduces the risk ofinfection. This action can operate by affecting the surface of thearticle, affecting surrounding tissues and fluids, or both. For example,use of endotracheal tubes containing a coating of the present inventionresulted in reduction of pneumonia occurrence as compared to uncoatedtubes. This reduction occurs even though tubes with a similar or thesame coating show limited or substantially no zone of inhibition in invitro testing for the microbes administered to test subjects.

[0069] The present invention further comprises methods of treatment anddelivery of substances as well as devices in which anywhere from 5-100%of the oligodynamic metals in the compositions are released in the first24 hours. A variety of release profiles from a single type of articleare therefore achieved. In some embodiments, between 75% and 100% of theoligodynamic metal in the coating is released in the first 24 hours. Inother embodiments, between 50% and 75% of the oligodynamic metal in thecoating is released in the first 24 hours. In other embodiments, between25% and 50% of the oligodynamic metal in the coating is released in thefirst 24 hours. In other embodiments, between 0% and 25% of theoligodynamic metal in the coating is released in the first 24 hours. Inother embodiments, about 75% of the oligodynamic metal is released inthe first 24 hours. In other embodiments, about 75% of the oligodynamicmetal is released in the first 24 hours. In other embodiments, about 40%of the oligodynamic metal is released in the first 24 hours. Otherembodiments involve releases over a longer period of time. In oneembodiment, about 38% is released the first day, and about 80% of theoligodynamic metal is release within 21 days. As used herein, release isdetermined using the procedures set forth in the elution tests inEXAMPLE 20 herein.

[0070] Another advantage of the coating compositions is the wetcoefficients of friction (COF) achievable. Coating compositions aremanipulated so that highly lubricious coatings are made or hydrophiliccoatings with little lubricity are made. Embodiments exist with anyachievable COF value. In some medical device embodiments, intermediaryCOF values ranging between about 0.100 and about 0.0300 are used toreduce the risk of unwanted slippage or movement of a coated articleafter placement in a location in the body such as a cavity or lumenwhile providing enough hydrophilicity to reduce tissue irritation andinflammation. In other embodiments where a highly lubricious surface isdesired, a COF ranging between about 0.040 and about 0.060 (after onehour immersion in water) is achieved. In some embodiments, a COF rangingbetween about 0.300 and about 0.400 (after one hour immersion in wateris achieved. In other embodiments, a COF ranging between about 0.100 andabout 0.200 after one hour immersion is achieved. In other embodiments,a COF ranging between about 0.200 and about 0.300 after one hourimmersion is achieved.(0.04-0.06) and a not so lubricious (0.1-0.3) andleave it at that. In another embodiment, a COF ranging between about0.337 and about 0.373 after one hour immersion is achieved. In otherembodiments, a COF ranging between about 0.040 and about 0.060 after onehour immersion is achieved. In other embodiments, a COF ranging betweenabout 0.100 and about 0.300 after one hour immersion is achieved. Asused herein, COFs are determined using the procedures set forth inEXAMPLE 21 herein. Although that example deals with endotracheal tubes,it may be used for any coated surface having the same dimensions.

[0071] Another advantage of the compositions of the present invention isthat the formation of colloids within the polymer composition producesultra-fine particles that possess a minimal particle size for the metalsalts. This minimal particle size retards settling and agglomeration.The use of colloids in the composition also permits incorporation ofhigher quantities of antimicrobial metal without the difficultiesassociated with the suspensions used in the prior art.

[0072] By reducing or eliminating the problems associated withconventional antimicrobial polymer compositions, the present inventionprovides reproducible compositions having specific antimicrobial ionconcentration with a specific antimicrobial ion release profiles thatcan be tailored through the specific salt combinations selected toprovide optimum antibiotic activity over an extended period of time. Forexample, compositions of the invention can be tailored to release thebulk of their oligodynamic agents within 5 days for a medical devicewith a short term use in the body, such as a wound drain, within 14 daysfor a device such as an endotracheal tube with an intermediary term use,or within 30 days for a device with a longer term use, such as a foleycatheter. Longer and shorter terms are possible.

[0073] The tailored delivery embodiment of the invention will now befurther described in terms of a polyurethane composition containing acolloid of specific silver salts. It is to be understood that this issimply an example of one embodiment of the invention and that one ofskill in the art, based upon the present disclosure, can pick and choosesalts having differing solubilities to provide a composition having asuitable release profile for a particular purpose.

[0074] A coating solution is formed from a 4.7% solution of a polyetherpolyurethane-urea block copolymer available from CardioTechInternational, Inc. in a mixture of THF/alcohol in a 75/25 ratio byweight. A sufficient quantity of 10% silver nitrate (AgNO₃) solution inwater is added to the copolymer solution to produce a final silverconcentration of approximately 15%, based on the weight of coatingsolids in the solution.

[0075] Aqueous solutions of sodium chloride, zinc iodide, sodiumcitrate, sodium acetate, and sodium lactate (each 1.0% solutions) areadded to the copolymer solution in sufficient amounts for each salt toreact with 15% of the silver nitrate present in the composition.Colloids of silver chloride, silver iodide, silver citrate, silveracetate, and silver lactate are formed in the final coating composition.The coating composition also contains 25% unreacted soluble silvernitrate, as well as the silver nitrate and zinc nitrate salt products.The differences in the solubility of the different salts in thecomposition will result in different and prolonged rates of release ofthe oligodynamic silver in the coating composition when a device coatedwith the composition is exposed to body fluid.

[0076] Silver nitrate is the most soluble of the salts present in thecomposition and will be released rapidly upon initial exposure of thecoating to body fluid. Sodium lactate, which has a lower solubility thansilver nitrate but a higher solubility than the other salts present,will be released next. Then, the silver acetate, followed by the silvercitrate, and then the silver chloride, and, lastly, the silver iodidewill be released from the coating composition based upon their relativesolubilities.

[0077] The initial release and the duration of release of theoligodynamic agents from the composition depends upon several factors.These factors include the relative water solubilities of the particularsalts formed in the colloid and the concentration of the salts in thecolloid. This release can range, for example, from a few days to severalmonths, and can be tailored through the choice and number of saltsformed in the composition for the intended purpose of the device to becoated.

[0078] The compositions of the invention can also be tailored to provideother desired properties, such as surface lubricity. Further, thecompositions may contain other medicinal or otherwise beneficial agents.

[0079] Incorporation of Additional Active Agents into the Copolymer

[0080] In some embodiments, the compositions of the present inventioncontain one or more additional active agents in addition to theoligodynamic metal salts or oxides. The active agents are eitherretained in the composition or released from the composition at adesired rate or having a desired release profile. Nonlimiting examplesof such active agents include antimicrobial agents, such asantibacterial agents, immune boosting agents, anticancer agents,angiogenic agents, polymyxins, antifungal agents, antiviral agents andantibiotics; growth factors, cytokines, immunoglobulins,pharmaceuticals, nutraceuticals, angiostatic agents, including, but notlimited to, antithrombogenic agents, antitumoral agents, growth factors,antiangiogenic agents, spermicides, anesthetics, analgesics,vasodilation substances, wound healing agents, plant extracts, and othertherapeutic and diagnostic agents. Other active agents useful in thepresent invention include herbicides, insecticides, algaecides,antifoulants, antifogging agents, and UV and other screening agents. Ofthese agents, those which can be used for medical applications arepreferred. The compositions can also contain salts of metals thatenhance the antimicrobial effect of the oligodynamic metal, such as theplatinum group metals, or other metals that promote galvanic action. Insome embodiments, the combination of additional antimicrobial compoundswith oligodynamic metal compounds provide for enhanced antimicrobialactivity, for example, by resulting in synergistic antimicrobialactivity.

[0081] The active agent is advantageously present in the composition inany amount. Desirable amounts include from about 0.1% to about 50% ofthe dry weight of the composition. Preferred amounts of the active agentare 1% to 30% of the composition based upon the dry weight of thecomposition.

[0082] The following agents have antimicrobial, antibacterial,antiviral, or antifungal activity and are examples of the types ofagents that can accompany the polymer and colloid in the composition ofthe present invention. It will be understood by one of ordinary skill inthe art that these are nonlimiting examples and that other active agentscan be incorporated into the copolymers of the present invention in amanner similar to the incorporation of the specifically recited agents.

[0083] The compositions of the present invention can also containadditional components. For example, the compositions can contain saltsof metals that enhance the antimicrobial effect of the oligodynamicmetal, such as the platinum group metals, or other metals that promotegalvanic action. Further, the composition can include agents that affectthe release of the oligodynamic metal.

[0084] In some embodiments, the active agent comprises one or morebiguanides, many of which have antimicrobial, antiviral, antibacterial,or antifungal activity, or some combination thereof. As used herein, theterm “biguanide” includes poly (hexamethylene biguanide) hydrochlorideand chlorhexidine compounds. Chlorhexidine is the term denoting thechemical compoundN,N″-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-Tetraazatetradecanediimidamide(CAS registry number 55-56-1). Chlorhexidine compounds includechlorhexidine free base as well as chlorhexidine salts, including butnot limited to chlorhexidine diphosphanilate, chlorhexidine digluconate,chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidinedichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate,chlorhexidine dinitrate, chlorhexidine sulfate, chlorhexidine sulfite,chlorhexidine thiosulfate, chlorhexidine di-acid phosphate,chlorhexidine difluorophosphate, chlorhexidine diformate, chlorhexidinedipropionate, chlorhexidine di-iodobutyrate, chlorhexidinedi-n-valerate, chlorhexidine dicaproate, chlorhexidine malonate,chlorhexidine succinate, chlorhexidine succinamate, chlorhexidinemalate, chlorhexidine tartrate, chlorhexidine dimonoglycolate,chlorhexidine mono-diglycolate, chlorhexidine dilactate, chlorhexidinedi-.alpha.-hydroxyisobutyrate, chlorhexidine diglucoheptonate,chlorhexidine di-isothionate, chlorhexidine dibenzoate, chlorhexidinedicinnamate, chlorhexidine dimandelate, chlorhexidine di-isophthalate,chlorhexidine isoethionate chlorhexidine di-2-hydroxy-napthoate, andchlorhexidine embonate. Preferred chlorhexidine salts include theacetates, formates, gluconates, hydrochlorides, isoethionates, lactates,and succinamates of chlorhexidine. These biguanide compounds are knownin the art and can be prepared by conventional methods. Numerous otherbiguanides are known and contemplated for use by the present invention.Biguanides can also form polymers. Use of these biguanide polymers isalso contemplated by the present invention.

[0085] Chlorhexidine is one preferred active agent because it alsoprovides antimicrobial activity. Any effective amount of chlorhexidinecan be used. In some embodiments, chlorhexidine is used in an amountgreater than zero 0 and up to about 50% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount greater than 0 and up to about 10% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 10% and about 50% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 2 and about 10% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 10% and about 20% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 20% and about 30% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 20% and about 30% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 25% and about 50% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 30% and about 40% based on total solids in thecomposition by weight. In some embodiments, chlorhexidine is used in anamount between about 40% and about 50% based on total solids in thecomposition by weight.

[0086] In some embodiments, the active agent comprises one or morechlorinated phenols, many of which have antimicrobial, antibacterial,antiviral, or antifungal activity, or some combination thereof.Chlorinated phenol compounds which may be used according to theinvention include but are not limited to parachlorometaxylenol,dichlorometaxylenol, triclosan (2,4,4′-trichloro-2 hydroxy di-phenylether), 2-chlorophenol, 3-chlorophenol, 4-chlorophenol,2,4-dichlorophenol, 2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol,pentachlorophenol, 4-chlororesorcinol, 4,6-dichlororesorcinol,2,4,6-trichlororesorcinol, alkylchlorophenols (includingp-alkyl-o-chlorophenols, o-alkyl-p-chlorophenols,dialkyl-4-chlorophenol, and tri-alkyl-4-chlorophenol),dichloro-m-xylenol, chlorocresol, o-benzyl-p-chlorophenol,3,4,6-trichlorphenol, 4-chloro-2-phenylphenol, 6-chloro-2-phenylphenol,o-benzyl-p-chlorophenol, and 2,4-dichloro-3,5-diethylphenol. Preferredchlorinated phenols include triclosan and parachlorometaxylenol.

[0087] In some embodiments, the active agent comprises one or morequaternary ammonium compounds including but not limited to monomeric andpolymeric quaternary ammonium compounds, many of which haveantimicrobial, antibacterial, antiviral, or antifungal activity or somecombination of the foregoing activities. Examples of quaternary ammoniumcompounds include, but are not limited to, benzalkonium chloride,benzethonium chloride, other benzalkonium or benzethonium halides,cetylpyridinium chloride, dequalinium chloride,N-myristyl-N-methylmorpholinium methyl sulfate,poly[N-[3-(dimethylammonio)propyl]-N′-[3-(ethyleneoxyethylenedimethylammonio)propyl]urea dichloride],alpha-4-[1-tris(2-hydroxyethyl)ammoniumchloride-2-butenyl]-omega-tris(2-hydroxyethyl)ammonium chloride,alpha-4-[1-tris(2-hydroxyethyl)ammoniumchloride-2-butenyl]poly[1-dimethyl ammoniumchloride-2-butenyl]-omega-tris(2-hydroxyethyl)ammonium chloride, poly[oxy-ethylene(dimethyliminio)ethylene (dimethyliminio)-ethylenedichloride], ethyl hexadecyl dimethyl ammonium ethyl sulfate, dimethylammonium ethyl sulfate, dimethylethylbenzyl ammonium chloride,dimethylbenzyl ammonium chloride, and cetyldimethylethyl ammoniumbromide. One preferred quaternary ammonium compound is benzalkoniumchloride.

[0088] In a further embodiment, the active agent comprises typicalantimicrobial agents, growth factors, cytokines, immunoglobulins, orpharmaceuticals and nutraceuticals. Typical active agents that areuseful in the present invention as antimicrobial, antiinfective,antiviral, and antibacterial agents include, but are not limited to,alexidine, aminoglycosides (such as gentamicin and Tobramycin),amoxicillin, amphotericin, ampicillin, bacitracin, beclomethasone,benzocaine, benzoic acid, beta-lactams such as pipracil and aztneonam,betamethasone, biaxin, cephalosporins such as ceftazidime, cetrimide,chloramphenicol, clarithromycin, clotrimazole, cyclosporin, docycline,erythromycin, ethylenediamine tetraacetic acid (EDTA), furazolidine,fusidic acid, , gramicidin, iodine and iodine complexes such as povidoneiodine and pluronic-iodine complex, macrolides, miconazole, minocycline,neomycin, nystatin, octenidine hydrochloride, ofloxacin,parachlorometaxylene, penicillin, pentoxifylline, phenolic compounds(e.g., orthophenylphenol), phenoxymethylpenicillin, picloxydine,polymixin, quinolone antibiotics (such as Norfloxacin, oxolinic acid,ciprofloxacin; Pefloxacin, Enoxacin, AM-833, Pipemidic acid andPiromidic acid,6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylicacid, naladixic acid, and salts thereof) rifampicin, sorbic acid,sulfamylon, sulfonamides, tetracycline, triclocarban, vancomycins,zithromax, derivatives, metabolites, and mixtures thereof, or compoundshaving similar antimicrobial activity.

[0089] Growth factors useful in the present invention include, but arenot limited to, transforming growth factor-α (“TGF-α”), transforminggrowth factor-β(“TGF-β”), vascular epithelial growth factor (“VEGF”),basic fibroblast growth factor, insulin-like growth factor (IGF),vascular endothelial growth factor (VEGF) and mixtures thereof.Cytokines useful in the present invention include, but are not limitedto, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11,IL-12, IL-13, TNF-α, and TNF-β. Immunoglobulins useful in the presentinvention include, but are not limited to, IgG, IgA, IgM, IgD, IgE, andmixtures thereof.

[0090] Some other specific examples of pharmaceutical agents that areuseful as active agents include, but are not limited to, nonoxynol 9,acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, AZT,alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin,amiloride, aminoacetic acid, aminodarone, amitriptyline, amlodipine,ascorbic acid, aspartame, astemizole, atenolol, benserazide,bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine,bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine,camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor,cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidime,ceftriaxone, cefuroxime, selegiline, chloramphenicol, chlor-pheniramine,chlortalidone, choline, cilastatin, cimetidine, cisapride, cisplatin,clavulanic acid, clomipramine, clozapine, clonazepam, clonidine,codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone,desogestrel, dexamethasone, dexpanthenol, dextromethorphan,dextropropoxiphen, diazepam, diclofenac, digoxin, dihydrocodeine,dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine,dipyridamole, dipyrone, disopyramide, domperidone, dopamine,doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol,ergotamine, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus,famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavinmononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine,flurbiprofen, furosemide, gallopamil, gemfibrozil, Gingko biloba,glibenclamide, glipizide, Glycyrrhiza glabra, grapefruit seed extract,grape seed extract, griseofulvin, guaifenesin, haloperidol, heparin,hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone,hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin,iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate,isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol,lactulose, lecithin, levocamitine, levodopa, levoglutamide,levonorgestrel, levothyroxine, lidocaine, lipase, imipramine,lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone,menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide,metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol,morphine, N-methylephedrine, naftidrofuryl, naproxen, nicardipine,nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine,nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone,norfloxacin, norgestrel, nortriptyline, omeprazole, ondansetron,pancreatin, panthenol, pantothenic acid, paracetamol, phenobarbital,derivatives, metabolites, and other such compounds have similaractivity. It should be noted that for any term in the foregoingparagraphs that is expressed as a singular term but is sometimesinterpreted as describing a class of compounds shall mean any of thegroup of compounds (e.g. all tetracyclines, all erythromycins, etc.)

[0091] Other pharmaceutical agents useful in the present inventioninclude, but are not limited to, other antibacterial, antiviral,antifungal, or antiinfective agents, antithrombogenic agents,anti-inflammatory agents, antitumoral agents, antiangiogenic agents,spermicides, anesthetics, analgesics, vasodilation substances, woundhealing agents, other therapeutic and diagnostic agents, and mixtures ofthese.

[0092] In another embodiment, the active agent comprises one or moreherbicide, insecticide, algaecide, antifoulant, antifogging agent, or UVor other screening agent.

[0093] The compositions of the present invention can contain anycombination of these or other active agents. The compositions can alsocontain additional components such as colorants, discolorationinhibitors, agents that affect the release or rate of release of theactive agent, surfactants, adhesion agents, agents that enhance theactivity of the active agent, solubilizing agents, agents that enhancethe lubricity of the compositions, and other agents which providebeneficial properties to the compositions.

[0094] In some embodiments, the compositions contain combinations of twoor more of the active agents. Any combination that produces desiredresults may be used. Some include (along with the polymer andoligodynamic metal colloid): a combination of a biguanide (especially achlorhexidine compound), a quaternary ammonium compound and achlorinated phenol (for example, chlorhexidine with benzalkoniumchloride and parachlorometaxylenol or triclosan); triclosan and anotheragent (for example ramicidin, polymixin, norfloxacin, sulfamylon,polyhexamethylene biguanide, alexidine, minocycline, iodine,benzalkonium chloride and rifampicin); chlorhexidine plus triclosan(optionally with silver sulfadiazine either as a part of the colloid orin addition to the colloid); combinations including a chlorhexidine freebase and triclosan or a complex resulting from the combination of thosetwo agents. Other examples include silver sulfadiazine (either as a partof the colloid or in addition to the colloid) and sodium piperacillin;silver sulfonamides (either as a part of the colloid or in addition tothe colloid) with piperacillin; silver (either as a part of the colloidor in addition to the colloid) with a chlorinated phenol and anotherantiinfective or antimicrobial agent.

[0095] Process for Preparing the Composition

[0096] In a second aspect, the present invention relates to a processfor producing the compositions of the invention. In general terms, theprocess comprises the formation of colloids of oligodynamic agents inpolymer solutions. The colloid can be formed first and then added to thepolymer composition or can be formed in situ in the polymer composition.Preferably, the colloid is formed in situ in the polymer composition.

[0097] The process of forming the colloids comprises, for example,combining two or more salts, wherein at least one of the salts is thesalt of an oligodynamic agent. These salts will be referred to as salt Aand salt B. Salt A comprises one or more oligodynamic agents. Salt Bcomprises one or more salts that can react with salt A to form acolloid. Salts A and B can be combined in any amount and in any order.In some embodiments, salt A is present in a stoichiometric amount or inexcess when compared to salt B. In some embodiments, salt B is presentin a stoichiometric amount or in excess when compared to salt A.

[0098] Optionally, additional components can be added to thecompositions. These components include, but are not limited to,additional oligodynamic agents, additional soluble salts, salts whichprovide galvanic action, and any other components which provide thecompositions with beneficial properties or enhance the antimicrobialactivity of the compositions. Such components include, but are notlimited to, antimicrobial agents, antibiotics, and other medicinalagents.

[0099] In one disclosed embodiment, the composition is produced byforming a solution, dispersion, or combination of solutions andsuspensions of one or more polymers. Next, a solution comprising salt Ais added to the polymer composition. Then, a solution comprising salt Bis added to the polymer composition to precipitate fine colloidalsalt(s) of the oligodynamic agent(s) of salt A. Where the oligodynamicagent is a metal salt, the metal cation of salt A reacts with the anionof salt B. Salt B is added to the polymer composition in an amountsufficient to react with some or all of salt A. Optionally, other saltsare then added in amounts to react with some or all of the remainingamount of salt A.

[0100] In another disclosed embodiment, salt B is added to the polymercomposition, followed by the addition of an excess or stoichiometricamount of salt A. In yet another embodiment, salts A and B can becombined to form a colloid which is then added to the polymercomposition.

[0101] The final polymer composition formed by these processes containsone or more colloidal salts, composed of the oligodynamic cations ofsalt A and the anions of salt B, and one or more soluble salts, composedof the anions of salt A and the cations of salt B. Additionally, othersalts may be added to the composition that do not react in solution butprovide some beneficial effect such as stabilization of the colloid,modification of antimicrobial ion release rate, promotion of galvanicaction, increase in antimicrobial effectiveness, or enhancement ofbiocompatibility. Further, other compounds may be added to thecomposition, including, but not limited to, medicinal agents,lubricants, nutritional agents, antioxidants, dyes and pigments, andother additives.

[0102] As noted above, any polymer can be used to form the compositionsof the present invention. When hydrophilic polymers are used, it ispreferable that the polymers be soluble in water or in organic solventscontaining some water. The ability to add water to the polymercomposition without precipitating the polymer allows the addition ofwater-soluble salts directly to the coating composition. The use ofwater in the polymer composition increases the solubility of the salts,resulting in the formation of finer, more stable colloids. However, ittakes longer for the coating compositions to dry when the water contentis very high. For this reason, the preferred amount of water in thehydrophilic polymer compositions is about 50% or less. Suchconcentrations provide for faster drying times while maintaining thebeneficial properties provided by the water in the composition.

[0103] In contrast, when hydrophobic polymers are used either alone orin combination with hydrophilic polymers, it is desirable to limit theamount of water present in the composition to avoid precipitation of thehydrophobic polymer with the colloid. In such instances the amount ofwater present in the polymer composition is preferably 1% or less. Whileit is possible to practice the invention in the absence of water in thecomposition, it is preferable to have some water present. Thus, whenhydrophobic polymers are employed in the present invention, thepreferred water content of the polymer compositions is between about0.1% and 1% by weight. It is advantageous to employ salts that aresoluble in alcohols or organic solvents when hydrophobic polymersemployed.

[0104] Examples of water-soluble silver salts suitable for use in thepresent invention include, but are not limited to, silver nitrate,silver acetate and silver lactate. Persons skilled in the art willrecognize that many of the “Salt B” salts listed above are soluble inwater and suitable for use as a water-soluble salt herein. Examples ofsalts which are soluble in alcohols and organic solvents include, butare not limited to, silver nitrate, sodium iodide, sodium lactate,sodium propionate, sodium salicylate, zinc chloride, zinc acetate, zincsalicylate, gold trichloride, gold tribromide, palladium chloride andhydrogen-hexachloroplatinate. Examples of alcohols that are useful inthe present invention include, but are not limited to, methanol,ethanol, propanol, isopropanol, and butanol. Examples of organicsolvents that can be used to form solutions of the oligodynamic saltsinclude, but are not limited to, acetone, tetrahydrofuran (THF),dimethylformamide (DMF), dimethlysulfoxide (DMSO), and acetonitrile.These organic solvents are especially useful when they contain a smallamount of water.

[0105] It is also possible to prepare polymer compositions fromsupercritical fluids. The most common of these fluids is liquefiedcarbon dioxide.

[0106] In a preferred embodiment, the polymer composition in which thecolloid is formed is a hydrophilic polyether polyurethaneurea. Thispolymer is a substantially noncovalently crosslinked reaction product ofone or more diols, water and an organic diisocyanate. The urea segmentsof the polymer provide improved strength, increased viscoelasticity, anddecreased water absorption. These polymers typically absorb water inamounts from 50 to 100% their weight while remaining strong and elastic.

[0107] Diols useful in the formation of these polymers include, but arenot limited to, medium and long chain poly(oxyethylene) glycols having anumber average molecular weights between 250 and 20,000. Example of suchdiols are “Carbowax” compounds sold by Union Carbide.

[0108] Organic diisocyanates useful to form these polymers include, butare not limited to, tetramethylene diisocyanate, hexamethylenediisocyanate, trimethylhexamethylene diisocyanate, dimer aciddiisocyanate, isophorone diisocyanate, diethylbenzene diisocyanate,decamethylene 1,10-diisocyanate, cyclohexylene 1,2-diisocyanate,cyclohexylene 1,4-diisocyanate, methylene bis(cyclohexyl-4-isocyanate),2,4- and 2,6-tolylene diisocyanate, 4,4-diphenylmethane diisocyanate,1,5-naphthaliene diisocyanate, dianisidine diisocyanate, tolidinediisocyanate, xylylene diisocyanate, andtetrahydronaphthalene-1,5-diisocyanate.

[0109] In another preferred embodiment, the polymer coating compositioncomprises a combination of a hydrophilic polyurethane, a polymer that issimilar or identical to the polymer substrate to be coated, and,optionally, other polymers which aid coating adhesion and physicalproperties. Antimicrobial salt colloids are prepared in this compositionas disclosed previously, with the exception that, depending on thesecond polymer used, some or all of the water used to prepare saltsolutions can be replaced with alcohols or other organic solvents toprevent precipitation of the second polymer. Another exception is thatthe salts elected must be soluble in solvents compatible with those inwhich the polymers are soluble. As an example of this preferredembodiment, a solution of a hydrophilic polyether polyurethaneurea inTHF can be combined with a solution of polyvinyl chloride (PVC) inmethylene chloride or THF in equal amounts. Then, silver nitrate can bedissolved in ethanol and added to the solution without precipitation.Ethanol is used to dissolve the silver nitrate instead of water becausePVC has a tendency to precipitate when water is added to the solution.Finally, a dilute solution of zinc chloride in ethanol/water can beslowly added to the polymer composition to produce a fine silverchloride colloid without precipitation of the PVC. The finalconcentration of water in the coating is less than 1%. The coatingsolution is then used to dip-coat PVC catheters. The finished coating iswell adhered, durable, lubricious when wetted, and contains colloidalantimicrobial salts.

[0110] In another embodiment, the polymer composition comprises ahydrophilic polymer as defined in application Ser. No. 09/189,240, filedNov. 10, 1998, herein incorporated by reference. In general, the polymeris a polyurethane-urea-silane copolymer prepared from the followingingredients: (1) one or more polyisocyanate, (2) one or more lubriciouspolymer having at least two functional groups, which may be the same ordifferent and are reactive with an isocyanate functional group, and (3)one or more organo-functional silanes having at least two functionalgroups, which may be the same or different and are reactive with anisocyanate functional group and another functional group that isreactive with a silicone rubber substrate. While these copolymers may beprepared in a variety of ways, preferably they may be prepared by firstforming a prepolymer from the polyisocyanate(s) and lubriciouspolymer(s) followed by reaction with the organo-functional silane(s). Acatalyst is optionally employed during reaction of the isocyanate withthe polyol.

[0111] Isocyanates useful to form these polymers include, but are notlimited to, 4,4′-diphenylmethane diisocyanate and position isomersthereof, 2,4- and 2,6-toluene diisocyanate (TDI) and position isomersthereof, 3,4-dichlorophenyl diisocyanate,dicyclohexylmethane-4,4′-diisocyanate (HMDI), 4,4′-diphenylmethanediisocyanate (MDI), 1,6-hexamethylene diisocyanate (HDI) and positionisomers thereof, isophorone diisocyanate (IPDI), and adducts ofdiisocyanates, such as the adduct of trimethylolpropane anddiphenylmethane diisocyanate or toluene diisocyanate.

[0112] Polyols useful to form these polymers include, but are notlimited to, polyethylene glycols, polyester polyols, polyether polyols,castor oil polyols, and polyacrylate polyols, including Desmophen A450,Desmophen A365, and Desmophen A160 (available from Mobay Corporation),poly(ethylene adipates), poly(diethyleneglycol adipates),polycaprolactone diols, polycaprolactone-polyadipate copolymer diols,poly(ethylene-terephthalate)diols, polycarbonate diols,polytetramethylene ether glycol, ethylene oxide adducts ofpolyoxypropylene diols, and ethylene oxide adducts of polyoxypropylenetriols.

[0113] Catalysts useful to form these polymers include, but are notlimited to, tertiary amines, such as N,N-dimethylaminoethanol,N,N-dimethyl-cyclohexamine-bis(2-dimethyl aminoethyl) ether,N-ethylmorpholine, N,N,N′,N′,N″-pentamethyl-diethylene-triamine, and1-2(hydroxypropyl) imidazole, and metallic catalysts, such as tin,stannous octoate, dibutyl tin dilaurate, dioctyl tin dilaurate, dibutyltin mercaptide, ferric acetylacetonate, lead octoate, and dibutyl tindiricinoleate.

[0114] Silanes useful to form these polymers include, but are notlimited to, N-beta-(aminoethyl)-gamma-aminopropyl-trimethoxy silane anddiamino-alkoxysilanes, such asN-(2-aminoethyl)-3-aminopropylmethyl-dimethoxy silane.

[0115] These polymers preferably have from 7 to 12% by weight silanebased upon the weight of the entire polymer. The preferred ratio ofisocyanate functional groups to alcohol or other isocyanate reactivefunctional groups is from 1.1:1 to 2:1. Viscosity of the polymersolution is a function of molecular weight of the polymer and the solidscontent of the solution and is controlled by addition of solvent to thesolution. The preferred copolymer solution for dip coating has akinematic viscosity in the range of about 1.5 cS to about 20 cS(centistokes), and a solids content in a range of about 0.4 to about 5.

[0116] In yet another embodiment, the polymer composition comprises asolution of a hydrophilic polymer as defined in U.S. Pat. No. 5,290,585,which is hereby incorporated by reference. The polymer is apolyurethane-polyvinyl pyrrolidone prepared by mixing the appropriateamounts of isocyanate, polyol, and polyvinyl pyrrolidone (PVP) stocksolution. Additional solvents can be added to adjust the viscosity andsolids content. Solids content may be in the range of 0.4 to 15% byweight, depending on the solvent used and other considerations. Thestoichiometric ratio of total NCO groups in the isocyanate to total OHgroups in the polyol may vary from 0.75 to 3.0. Preferably, theisocyanate has at least two NCO groups per molecule and the polyol hasat least two OH groups per molecule. The ratio of polyurethane formed insitu to PVP ranges from 0.05 to 3.0 by weight.

[0117] The PVP employed to form these polymers preferably has a meanmolecular weight from about 50,000 to 2.5 million Daltons. Specificpreferred PVP polymers are Kollidon 90, Luviskol K90, Luviskol K80, andLuviskol K60, all available from BASF Corp. (Parsippany, N.J.) andPlasdone 90, PVP K90, and PVP K120, all available from GAF Corporation.

[0118] Isocyanates suitable to form these polymers include, but are notlimited to, polymethylenepolyphenyl isocyanate, 4,4′-diphenylmethanediisocyanate and position isomers thereof, 2,4-tolylene diisocyanate andposition isomers thereof, 3,4-dichlorophenyl diisocyanate, isophoroneisocyanate, and adducts or prepolymers of isocyanates, such as theisocyanate prepolymer available as Vorite 63 from CasChem, Inc.(Bayonne, N.J.). Other examples of polyisocyanates useful in the presentinvention are those listed in ICI Polyurethanes Book, by George Woods,published by John Wiley and Sons, New York, N.Y. (1987).

[0119] Polyols useful to form these polymers include, but are notlimited to, polyester polyols, polyether polyols, modified polyetherpolyols, polyester ether polyols, castor oil polyols, and polyacrylatepolyols, including Desmophen A450, Desmophen A365, and Desmophen A160available from Mobay Corporation (Pittsburgh, Pa.). Preferred polyolsinclude castor oil and castor oil derivatives, such as DB oil,Polycin-12, Polycin 55, and Polycin 99F available from CasChem, Inc.Preferred diols include, but are not limited to, Desmophen 651A-65,Desmophen 1300-75, Desmophen 800, Desmophen-550 DU, Desmophen-1600U,Desmophen-1920D, and Desmophen-1150, available from Mobay Corporation,and Niax E-59 and others available from Union Carbide (Danbury, Conn.).

[0120] Suitable solvents for use in the formation of these polymers arethose which are capable of dissolving the isocyanate, the polyol, andthe polyvinyl pyrrolidone without reacting with any of these components.Preferred solvents include, but are not limited to, methylene chloride,dibromomethane, chloroform, dichloroethane, and dichloroethylene.

[0121] When a composition containing this polymeric solution is to beused as a coating, the coating is cured, after application to thesubstrate, at a temperature in the range of approximately 75° F. toapproximately 350° F. for a period in the range of about 2 minutes toabout 72 hours.

[0122] The process of the invention will now be further described interms of the formation of a colloid of silver chloride from silvernitrate and sodium chloride in a polyurethane polymer coating solution.It is to be understood that this is simply an example of one preferredembodiment of the invention and that any polymer or combination ofpolymers and any mixture of salts that will form a colloid within thepolymer solution can be employed in the present invention.

[0123] First, a 4.7% solution of a polyether polyurethane-urea blockcopolymer is prepared in a mixture of THF/ethanol in a 75/25 ratio byweight. A sufficient quantity of 10% silver nitrate (AgNO₃) solution inwater is added to the CardioTech copolymer solution to produce a finalsilver concentration of approximately 15%, based on coating solids inthe solution. An aqueous solution of 1.0% sodium chloride (NaCl) is thenslowly added to the solution with stirring in an amount sufficient toreact with 50% of the AgNO₃. The NaCl reacts with the AgNO₃ to produce acolloidal suspension of the poorly water soluble salt, AgCl, and thesoluble salt, NaNO₃, from half of the AgNO₃. The amount of water in thefinal coating solution is about 30% of the total solvent weight. Thefinal polymer concentration in the coating solution is 3.3%, based uponsolvent and polymer weights.

[0124] A 16 Fr latex Foley catheter can then be coated with thecomposition by dipping it into the composition solution, withdrawing itat a controlled rate and drying it using standard methods. The finishedcoating contains both the water soluble, and therefore fast releasing,AgNO₃, and the water insoluble, and therefore slow releasing, AgCl.

[0125] Preparation of Compositions Containing an Additional Active Agent

[0126] The active agent can be incorporated into the compositions of thepresent invention by any suitable method. For example, in oneembodiment, the active agent is mixed with the components of thecopolymer composition in a solvent suitable for both the composition andthe active agent. Such solvents include, but are not limited to, thosediscussed above in the process for making the composition.

[0127] In another embodiment, the active agent or agents are mixed withthe monomers that form the copolymer prior to polymerization. In thisembodiment it is desirable that the active agent will not be deactivatedby polymerization conditions and will not interfere with polymerization.The monomeric components are then polymerized by methods known in theart.

[0128] In yet another embodiment, the copolymer is formed as describedabove, followed by addition of the active agent to the copolymersolution.

[0129] The active agent may be soluble or insoluble in the polymercompositions of the invention or may be a combination of soluble andinsoluble agents. Solubilized active agents may be achieved by anymeans. In some embodiments, the active agent is first dissolved in asuitable solvent before addition to any of the solutions used to producethe compositions of the invention. In some embodiments, an active agentsis solubilized by adding the dry active agent directly to a solution ofthe compositions of the invention, in which it then dissolves.

[0130] Insoluble active agents are used in some embodiments of theinvention. In one embodiment, the active agent is dispersed into aseparate solvent before addition to the solutions of the invention. Inanother embodiment, the active agent is dispersed directly into anysolution of the used to produce the compositions of the invention.Combinations of these techniques are also used.

[0131] Uses Of The Composition

[0132] In a third aspect, the present invention relates to an article ofmanufacture. In a preferred embodiment, the antimicrobial compositioncan be used as a coating on a preformed article to provide antimicrobialactivity to the surface of the article and to the environmentsurrounding the article through the continual release of oligodynamicions. Any article can be coated with the antimicrobial compositions ofthe present invention. The composition is particularly suited for theproduction of medical devices, which include, but are not limited to,catheters (as used throughout this application, the term “catheter”denotes any type of catheter including, but not limited to, urinarycatheters, vascular catheters, dialysis catheters, and port catheters),cannulae, stents, guide wires, implant devices, contact lenses, IUDs,peristaltic pump chambers, endotracheal tubes, gastroenteric feedingtubes, arteriovenous shunts, condoms, oxygenator and kidney membranes,gloves, pacemaker leads, and wound dressings.

[0133] The coatings can be applied to all or part of any surface orgroup of surfaces on an article. In some embodiments, one or more entiresurfaces of an article are coated. In other embodiments, only part ofone or more surfaces is coated. In other embodiments, some surfaces arecoated in their entirety while other surfaces are coated only partially.Any combination of surfaces, partial surfaces, or both may be selectedfor coating or remaining uncoated. Partial coating may be accomplishedby, for example, dipping only part of an article into a coatingcomposition or spraying a coating composition on to only a part of thearticle.

[0134] For example, in some embodiments in which underlying articles aretransparent while coatings are opaque or translucent, a portion of thearticle may remain uncoated to allow visual inspection of the inside ofthose portions of the article, including any lumen therein. Inembodiments involving endotracheal tubes, for example, it may bedesirable to leave a portion of the tube that will be outside the mouthof the patient uncoated so that it is possible to view the inner lumenof the tube to determine whether a patient is breathing properly.

[0135] An example of such an endotracheal tube 10 is shown in FIG. 1.The endotracheal tube comprises an elongate tubular body 12 having anupper end 14 and a lower end 16. A connector 18 is coupled to the body12 at its upper end 14 for connecting the endotracheal tube to amechanical ventilator. An inflatable cuff 20 is provided adjacent thelower end 16 of the endotracheal tube 10. The cuff 10 is inflated bymeans of a valve 30, which is in fluid communication with the cuff 20 bymeans of an inflation tube 32 and an inflation lumen (not shown) formedin the wall of the tubular body 12. The cuff is inflated in theconventional manner, such as by infusing a air through the valve 30 witha syringe.

[0136] The inner and outer surfaces of the endotracheal tube 10 aredipped in a coating solution, such as the one of the compositionsdescribed above, which forms an opaque or translucent layer when appliedto the tube and permitted to dry. The dipping process coats both theinterior and exterior surfaces of the endotracheal tube 10. However, toprevent the entire endotracheal tube from becoming opaque, a portion 40adjacent the upper end 14 of the tubular body 12 is not coated. Theuncoated portion may be provided in any suitable manner, such as by notdipping the upper portion 40 into the coating solution, or by maskingthe wall of the endotracheal tube adjacent the upper end to prevent thecoating composition from coating the upper portion.

[0137] The resulting endotracheal tube has an opaque coating applied tosubstantially the entire endotracheal tube except for the uncoatedportion 40 which, when a patient is intubated and the tube is used inits normal manner, resides outside the patient. The physician can thusvisualize the presence or absence of moisture or “fogging” through theuncoated walls of the upper portion 40, as an indication of whether thepatient is breathing properly. In the disclosed embodiment of theendotracheal tube 10, the uncoated portion 40 is approximately fivecentimeters in length. It will be understood, however, that the portion40 can be shorter or longer, as appropriate, so long as at least asufficient portion of the tube is coated to provide intendedantimicrobial or other effects, and so long as at least a part of theuncoated portion 40 resides outside the patient when the tube is usednormally and in its intended manner.

[0138] It will also be appreciated that the disclosed practice ofleaving a portion of the endotracheal tube uncoated so as to visualizemoisture or fogging through the walls of the tube is not limited to thedisclosed coatings but includes other coatings, including but notlimited to antimicrobial, bactericidal and germicidal coatings, coatingscontaining active agents of any type, lubricious coatings, and the like,especially coatings which are translucent or opaque when applied to thetube and permitted to dry.

[0139] While the embodiment disclosed above contemplates the coating ofboth the interior and exterior surfaces of the endotracheal tube 10, theinvention is equally applicable to coatings which are applied only tothe exterior surface or only to the interior surface of the tubular body12.

[0140] In some embodiments, the composition of the invention is preparedas a high solids solution and used alone or mixed with other polymers toform an article rather than a coating on an article. Polymers which areuseful to form the articles of the invention include, but are notlimited to, natural and synthetic rubber, especially latex rubber,acrylonitrile rubber, PVC plastisol, PVC, polyurethanes, silicone,polycarbonates, acrylates, polyamides, polypropylenes, polyethylenes,polytetrafluoroethylenes, polyvinylacetate, poly(ethyleneterephthalate), polyesters, polyamides, polyureas, styrene-blockcopolymers, polymethyl methacrylate, acrylic-butadiene-styrenecopolymers, polystyrene, cellulose, and derivatives and copolymers ofany of the above.

[0141] As nonlimiting examples, compositions of the invention can beadmixed into latex rubber for fabrication of catheters, gloves, andother dipped latex products by standard form dipping methods, and vinylplastisols can be mixed with compositions of the invention to providedippable and castable antimicrobial PVC devices. Thus, the final articlecan be composed of one or more of the compositions of the presentinvention in admixture with other polymeric components.

[0142] Alternatively, compositions of the invention can be formulatedinto high solids coating compositions that can be used to dip-fabricatea variety of medical devices, such as catheters, stents, gloves,condoms, and the like.

[0143] By another method, compositions of the invention can be dried andmelt processed, for example, by injection molding and extrusion.Compositions used for this method can be used alone or compounded withany other melt-processable material for molding and extrusion ofantimicrobial articles.

[0144] When used as a coating, the compositions can be applied by anymeans, including those methods known in the art. For example, thecompositions can be brushed or sprayed onto the article, or the articlecan be dipped into the composition. For example, the article can bedipped into the antimicrobial polymer solution at a rate of about 10-80inches per minute (ipm), preferably about 40 ipm. The article is allowedto remain in the antimicrobial polymer solution for a period of about0-30 seconds, preferably about 5-15 seconds. The article is thenwithdrawn at a rate of about 10-80 ipm, preferably about 15-30 ipm. Oncethe article has been coated with the copolymer of the invention, it isallowed to air dry for a period of at least about 10 minutes beforedrying is completed in an oven for a period of about 5-60 minutes at atemperature in the range of about 40-100° C. Preferably, oven dryingoccurs for a period of about 15 minutes at a temperature of about 50° C.The coated article can optionally be dried with a hot air stream at atemperature in the range of approximately 40° C. to approximately 100°C. for a period of about 5-60 minutes to remove residual solvent.Persons skilled in the art will understand that the parameters in theforegoing paragraph are merely examples and will vary based on thecomposition of the substrate and coating and the desired features of thecoated objects.

[0145] The invention allows manipulation of the amount of oligodynamicmetal compounds contained in the article per surface area (expressed inunits such as micrograms of oligodynamic metal compound per squarecentimeter of surface area, or μg/cm²). Manipulation of this parameterprovides an additional means of controlling release rate or releaseprofile. Any achievable concentration may be used. In some embodiments,the article contains between about 40 and about 50 μg/cm² oligodynamicmetal compound or compounds. In some embodiments, the article containsbetween about 50 and about 100 μg/cm² oligodynamic metal compound orcompounds. In some embodiments, the article contains between about 50and about 75 μg/cm² oligodynamic metal compound or compounds. In someembodiments, the article contains between about 50 and about 60 μg/cm²oligodynamic metal compound or compounds. In some embodiments, thearticle contains between about 25 and about 50 μg/cm oligodynamic metalcompound or compounds. In some embodiments, the article contains betweenabout 30 and about 40 μg/cm² oligodynamic metal compound or compounds.In some embodiments, the article contains between about 20 and about 30μg/cm² oligodynamic metal compound or compounds. In some embodiments,the article contains between about 25 and about 30 μg/cm² oligodynamicmetal compound or compounds. In some embodiments, the article containsbetween about 10 and about 20 μg/cm² oligodynamic metal compound orcompounds. In some embodiments, the article contains between about 15and about 20 μg/cm² oligodynamic metal compound or compounds. In someembodiments, the article contains between about 10 and about 15 μg/cm²oligodynamic metal compound or compounds. In some embodiments, thearticle contains between about 5 and about 15 μg/cm² oligodynamic metalcompound or compounds. In some embodiments, the article contains betweenabout 5 and about 10 μg/cm² oligodynamic metal compound or compounds. Insome embodiments, the article contains between about 4 and about 7μg/cm² oligodynamic metal compound or compounds. In some embodiments,the article contains between about 11 and about 14 Ag/cm² oligodynamicmetal compound or compounds. In some embodiments, the article containsabout 13 μg/cm² oligodynamic metal compound or compounds. In someembodiments, the article contains about 8 μg/cm² oligodynamic metalcompound or compounds. In some embodiments, the article contains about 8Ag/cm² oligodynamic metal compound or compounds. In some embodiments,the article contains about 28 Ag/cm² oligodynamic metal compound orcompounds. The foregoing ranges are obtained with coated articles aswell as with articles formed from the composition.

[0146] Use of the Compositions Containing an Additional Active Agent

[0147] As discussed above, in one embodiment, the compositions of thepresent invention can be coated onto the surface of a substrate or usedto form an article. Preferred articles are medical devices. The same istrue when the composition comprises one or more active agents.

[0148] In one embodiment, an article is first coated with a layer ofsilver as described, for example in U.S. Pat. Nos. 5,395,651; 5,747,178;and 5,320,908 to Sodervall et al., the disclosures of which areincorporated by reference herein. The composition of the presentinvention is then coated over the silver coated article in a manner asdescribed above.

[0149] In some embodiments, the compositions of the invention comprisingthe active agent are used in combination with one or more additionalcoating compositions to coat a surface. Alternatively, the compositionis used to form an article to which one or more coatings is thereafterapplied. The following is a description of some of the possible coatingcombinations contemplated by the present invention. This descriptionexemplifies the invention in terms of two layers, a primer or base coatand a top coat. However, the invention encompasses the use of more thantwo layers, any of which can include the active agents of the presentinvention. The following combinations of coatings are not intended to beexclusive. One having ordinary skill in the art with the followinginformation would readily recognize additional combinations and becapable of practicing the present invention with such additionalcombinations. Any combination of coatings may be used.

[0150] Some multi-coating embodiments comprise the use of twocompositions to provide two distinct coatings on the device or a formedarticle and a coating. It should be understood that the invention isalso practiced with multiples layers following the same principles asdescribed below.

[0151] The coatings may contain the same composition or differentcompositions, so long as one of the coatings comprises the compositionof the present invention. Where two or more coating layers are employedin the invention, it is convenient to refer to the coating layer closestto the substrate surface as a primer or base coat and to the coatinglayer most exterior as the top coat.

[0152] The compositions of the present invention can be employed as thebase coat, the top coat, or both. They can also be employed asintermediate coating layers when used with other coatings of the presentinvention or known in the art.

[0153] In some embodiments, the substrate base coat comprises apolymeric composition that improves adherence of the other coatinglayers to the article. In some embodiments, top coats that provide a dryelastic coating that becomes lubricious when wet.

[0154] Any of the coating layers can comprise one or more active agentsin addition to the colloid. Where multiple coatings contain an activeagent, the active agents in the coatings may be the same or different.Further, one or more of the coatings can contain additional agents thatprovide advantageous properties to the device. For example, any of thecoatings, regardless of whether it contains an active agent, can alsocontain agents that affect the release or rate of release of the activeagent. The coatings can also contain agents that improve adhesion of thecoatings to the substrate or to the base coat, improve wet lubricity ofthe surface, inhibit discoloration of the compositions containing activeagents that discolor, provide additional therapeutic activity, enhancethe activity of the active agent, provide galvanic action foroligodynamic metal, and the like.

[0155] Further, the particular polymeric compositions of the coatingscan be designed to provide some of the properties listed above, such asimproved adhesion, improved lubricity, or to enhance or inhibit releaseof the active agent.

[0156] As with coatings that do not contain active agents, the preferredsubstrates are medical devices. Such medical devices include, forexample, catheters, guidewires, implant devices, contact lenses, IUDs,peristaltic pump chambers, endotracheal tubes, gastroenteric feed tubes,arteriovenous shunts, condoms, and oxygenator and kidney membranes. Useof particular active agents in the various coating layers providesparticular beneficial effects. For example, use of antibiotics orantimicrobials, inhibits the adherence of bacteria to the surface of thedevice and can prevent infection in the surrounding tissue.

[0157] Although the compositions of the present invention have manyapplication in connection with medical devices, their use is not limitedto such embodiments. In some embodiments, the compositions of thepresent invention are used to coat consumer products and other surfacesto provide an active agent on the surface. The compositions may be usedfor any suitable purposes. In some embodiments, the compositions of thepresent invention are used to coat glass beads, chromatography packingmaterial, and other substances for use as diagnostic agents. An exampleof such embodiments is use of active agents incorporated in suchcompositions that can detect the desired chemical or substance to bedetected. Detection of the appropriate substance can be performed byconventional methods, such as ELISA assays, radioimmunoassays, NMR,fluorescent spectroscopy, and the like.

[0158] While it is preferred to dip coat medical devices, such ascatheters and stents, the compositions of the present invention can becoated by any other means including, but not limited to spray or brushcoatings.

[0159] Other applications for which the copolymer compositions of thepresent invention are useful include coating the compositions ontosurfaces in contact with bodies of water such as the walls of pools orspas, the hulls of boats or ships, and the like to provide algaecidicactivity, antifoulant activity, or both. For example, the coatings ofthe invention can be applied to ship hulls to prevent attachment ofinvertebrate encrustation (e.g. arthropod or molluscan encrustation), orto pool liners to prevent bioslime.

[0160] Other Methods of Use, Including Substance Delivery, and Treatment

[0161] Methods of use of compositions of the present invention andarticles comprising those compositions also include, but are not limitedto, methods of delivering oligodynamic metals, in forms including, butnot limited to, ions, salts and oxides of one or more oligodynamicmetals or combinations thereof, to a desired location as well as methodsof treatment of cells, tissues, and organisms.

[0162] In some embodiments in which compositions contain additionalactive agents, the compositions of the present invention can also beused as delivery agents to deliver one or more active agents to adesired location. The method includes delivery of any active agent orcombination of agents, including any of the active agents listed above.In some embodiments, the methods provide delivery of beneficial agentsto patients. For such uses, the compositions of the present inventionare used, for example, as coatings on substrates, such as medicaldevices, bandages, or devices known in the art for topical delivery ofpharmaceutical agents or to form the articles or parts of such articles.

[0163] Some embodiments of methods involve delivery of substances to oneor more desired locations. Delivered substances include, but are notlimited to, compositions comprising both the polymers and the colloidsof oligodynamic compounds, the oligodynamic metal compounds themselves,or oligodynamic metal ions. In embodiments in which the compositioncontains one or more additional active agents, the delivered substancesinclude such agent or agents. Preferred locations include, but are notlimited to, an orifice, tissue, cavity, fluid, or other component of thebody of an organism. Other preferred methods include in vitro deliveryto tissues, tissue cultures, suspensions of cells, or other substancesor preparations. In some embodiments, methods include placing acomposition of the present invention in conditions effective to causedelivery of one or more oligodynamic metals or ions, salts or oxidesthereof (optionally including additional active agents as well) to thedesired location. Examples of such conditions include, but are notlimited to an aqueous fluid that will allow diffusion of theoligodynamic metal ions or one or more other active agents from thecomposition and a location in the body of an organism that will allowdiffusion of oligodynamic metal salts or oxides or one or more otheractive agents into a tissue or a fluid in the body.

[0164] Methods of the present invention are useful in treatments oforganisms, cells, or tissues. An example of such methods involvesplacing the polymer composition comprising one or more oligodynamicmetal compounds and one or more other active agents, or articlescomprising such compositions, under conditions effective to deliver ionsor compounds of oligodynamic metals to the target organisms, cells, ortissues. Such compositions may, for example, be implanted, administered,inserted, or otherwise placed in conditions effective to cause theoligodynamic metal salts or ions or one or more other active agents tobe delivered to the cells, tissue, organisms, or parts of organisms.Examples of treatments include, but are not limited to, for example,antifungal treatments, antiviral treatments, anti-inflammatorytreatments, anesthetic treatments, antiseptic treatments, analgesictreatments, stimulant treatments, depressant treatments, tranquilizertreatments, hormone administration, germicidal treatments, antiprotozoaltreatments, antiviral treatments, antineoplastic treatments,antiparasitic treatments, antirheumatic treatments, antibacterialtreatments, emetic treatments, antiseptic treatments, treatments forinhibiting restenosis, methods of inhibiting healing, methods ofreducing thrombus formation, methods of anticoagulation, methods ofreducing encrustation, methods of providing topical protection, methodsof deodorization (e.g. of wounds or ulcers), methods of preventing orcombating infection, methods of preventing or combating microbial orparasitic infestation, methods of promoting healing, methods ofproducing a styptic or astringent effect, methods of causing formationof eschars or scars, methods of preventing the formation of eschars orscars, methods of contraception, and methods of treating ulcers, slowlygranulating wounds, vaginitis, fistulas, dermatitis, or popodermatitis.Additional examples regarding treatments are disclosed in the discussionof the effects of the composition above, and in the example below.

[0165] Any of the terms used in the preceding paragraph to describeeffects or treatments are defined to have their broadest possiblemeanings. Terms that refer to being “anti” a type of target organism oragent (e.g. antimicrobial, antiviral, antibacterial) refers to havingany deleterious effects upon those organisms or their ability to causesymptoms in a host or patient. Examples include, but are not limited to,inhibition or prevention of growth or reproduction, killing, andinhibiting any metabolic activity of the target organisms. Terms thatrefer to being “anti” a type of symptom or condition, or as being a“treatment” for a type of condition or symptom, include but are notlimited to any effect that prevents, reduces, cures, accelerates cure orhealing, or reduces the severity of one or more conditions or symptoms.

[0166] As discussed above, the use of salts and oxides of differingsolubilities allows control of release profiles of oligodynamic metals.The methods, compositions, and articles herein may also include othermeans of controlling release profiles. In some embodiments, articlescomprising the compositions are shaped in a specific way to affectrelease profile. For example, diffusion of oligodynamic metals (and,optionally, one or more other active agents) from polymer compositionscomprising the salts is enhanced by fragmenting or pulverizing thepolymer compositions. In some embodiments, pulverized compositions areapplied to a wound site, ingested, or formed into another shape such asa capsule or a tablet. In other embodiments, release is affected byapplying an elevated or reduced temperature, an electric field, amagnetic field, or an electric current to the oligodynamic metalcompositions before, during, or after application. Release is alsoaffected by coating compositions and articles with other substances orpreparing laminates in which layers have different release profiles orcombinations thereof. Layering an object with one or more coatings thatdissolve over a given period of time, for example, affords another levelof control of release profile. The coatings, envelopes, and protectivematrices may be made, for example, from polymeric substances, waxes,oligomeric substances, or combinations thereof. The compositions mayalso contain additional chemicals that affect the release profile of theoligodynamic metal compounds.

[0167] Methods of treatment and methods of delivery of oligodynamicmetal salts and oxides (and, optionally, one or more other activeagents) can include release from articles containing the compositionsincluding, for example, catheters, cannulae, stents, guide wires,implant devices, contact lenses, IUDs, peristaltic pump chambers,endotracheal tubes, gastroenteric feeding tubes, arteriovenous shunts,condoms, oxygenator and kidney membranes, gloves, pacemaker leads, andwound dressings. The compositions of the present invention may becombined with pharmaceutically or cosmetically acceptable carriers andadministered as compositions in vitro or in vivo. Forms ofadministration include but are not limited to implantation or insertionof a medical device comprising the composition, injections, solutions,lotions, slaves, creams, gels, implants, pumps, ointments, emulsions,suspensions, microspheres, particles, microparticles, nanoparticles,liposomes, pastes, patches, tablets, transdermal delivery devices (suchas patches), sprays, aerosols, or other means familiar to one ofordinary skill in the art. Such pharmaceutically or cosmeticallyacceptable carriers are commonly known to one of ordinary skill in theart. Pharmaceutical formulations of the present invention can beprepared by procedures known in the art using well known and readilyavailable ingredients. For example, the compounds can be formulated withcommon excipients, diluents, or carriers, and formed into tablets,capsules, suspensions, powders, and the like. Examples of excipients,diluents, and carriers that are suitable for such formulations includethe following: fillers and extenders (e.g., starch, sugars, mannitol,and silicic derivatives); binding agents (e.g., carboxymethyl celluloseand other cellulose derivatives, alginates, gelatin, andpolyvinyl-pyrrolidone); moisturizing agents (e.g., glycerol);disintegrating agents (e.g., calcium carbonate and sodium bicarbonate);agents for retarding dissolution (e.g., paraffin); resorptionaccelerators (e.g., quaternary ammonium compounds); surface activeagents (e.g., cetyl alcohol, glycerol monostearate); adsorptive carriers(e.g., kaolin and bentonite); emulsifiers; preservatives; sweeteners;stabilizers; coloring agents; perfuming agents; flavoring agents; drylubricants (e.g., talc, calcium and magnesium stearate); solid polyethylglycols; and mixtures thereof.

[0168] The terms “pharmaceutically or cosmetically acceptable carrier”or “pharmaceutically or cosmetically acceptable vehicle” are used hereinto mean, without limitations, any liquid, solid or semi-solid, includingbut not limited to water or saline, a gel, cream, salve, solvent,diluent, fluid ointment base, ointment, paste, implant, liposome,micelle, giant micelle, and the like, which is suitable for use incontact with living animal or human tissue, desirably without causingexcessive adverse physiological or cosmetic responses, and withoutexcessively interacting with the other components of the composition ina deleterious manner. Other pharmaceutically or cosmetically acceptablecarriers or vehicles known to one of skill in the art may be employed tomake compositions for delivering the molecules of the present invention.

[0169] In some embodiments, formulations are constituted so that theyrelease the active ingredient only or preferably in a particularlocation, over a period of time, or a combination thereof. Suchcombinations provide yet a further mechanism for controlling releasekinetics.

[0170] Methods of in vivo administration of the compositions of thepresent invention, or of formulations comprising such compositions andother materials such as carriers of the present invention that areparticularly suitable for various forms include, but are not limited to,urethral administration, oral administration (e.g. buccal or sublingualadministration), anal administration, rectal administration,administration as a suppository, topical application, aerosolapplication, inhalation, intraperitoneal administration, intravenousadministration, transdermal administration, intradermal administration,subdermal administration, intramuscular administration, intrauterineadministration, vaginal administration, administration into a bodycavity, implantation, surgical administration at the location of a tumoror internal injury, administration into the lumen or parenchyma of anorgan, and parenteral administration. Techniques useful in the variousforms of administrations above include but are not limited to, topicalapplication, ingestion, inhalation, insertion, surgical administration,injections, sprays, transdermal delivery devices, osmotic pumps,applying directly on a desired site, or other means familiar to one ofordinary skill in the art. Sites of application can be external, such ason the epidermis or into an orifice, or internal, for example a gastriculcer, a surgical field, or into the lumen of a duct or organ, orelsewhere.

[0171] The compositions of the present invention can be applied in theform of creams, gels, solutions, suspensions, liposomes, particles, orother means known to one of skill in the art of formulation and deliveryof therapeutic and cosmetic compounds. Ultrafine size particlescontaining the composition can be used for inhalation delivery. Someexamples of appropriate formulations for subcutaneous administrationinclude but are not limited to implants, depot, needles, capsules, andosmotic pumps. Some examples of appropriate formulations for vaginaladministration include but are not limited to creams, cervical caps, andrings. Some examples of appropriate formulations for oral administrationinclude but are not limited to: pills, liquids, syrups, and suspensions.Some examples of appropriate formulations for transdermal administrationinclude but are not limited to creams, pastes, patches, sprays, andgels. Formulations suitable for parenteral administration include butare not limited to aqueous and non-aqueous sterile injection solutionswhich may contain anti-oxidants, buffers, bacteriostats and soluteswhich render the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets commonly used by one of ordinary skill inthe art.

[0172] Embodiments in which the compositions of the invention arecombined with, for example, one or more pharmaceutically or cosmeticallyacceptable carriers or excipients may conveniently be presented in unitdosage form and may be prepared by conventional pharmaceuticaltechniques. Such techniques include the step of bringing intoassociation the compositions containing the active ingredient and thepharmaceutical carrier(s) or excipient(s). In general, the formulationsare prepared by uniformly and intimately bringing into association theactive ingredient with liquid carriers. Preferred unit dosageformulations are those containing a dose or unit, or an appropriatefraction thereof, of the administered ingredient. It should beunderstood that in addition to the ingredients particularly mentionedabove, formulations comprising the compositions of the present inventionmay include other agents commonly used by one of ordinary skill in theart. The volume of administration will vary depending on the route ofadministration. For example, intramuscular injections may range involume from about 0.1 ml to 1.0 ml.

[0173] This invention is further illustrated by the following examples,which are not to be construed in any way as imposing limitations uponthe scope of the invention.

EXAMPLES Example 1

[0174] To form the coating solution, a 4.7% solution of a polyetherpolyurethane-urea block copolymer available from CardioTechInternational, Inc. was prepared in a mixture of THF/alcohol in a 75/25ratio by weight. A sufficient quantity of 10% silver nitrate (AgNO₃)solution in water was added to the CardioTech copolymer solution toproduce a final silver concentration of approximately 15%, based on theweight of coating solids in the solution. An aqueous solution of 1.0%sodium chloride (NaCl) was added to the solution in an amount sufficientto react with 50% of the AgNO₃ to produce a colloid of the poorly watersoluble salt, AgCl, from half of the AgNO₃ in the coating solution. TheNaCl solution was added slowly to the polymer solution and the solutionbegan to turn cloudy with the formation of the fine colloidal AgCl. Theamount of water in the final coating solution was about 30% of the totalsolvent weight. The final polymer concentration in the coating solutionwas 3.3%, based upon solvent and polymer weights.

[0175] A 16 Fr latex Foley catheter was then coated by dipping it intothe coating solution, withdrawing it at a controlled rate to control thethickness of the coating and drying the catheter coating using standardmethods. The finished coating contained both the water soluble, andtherefore fast releasing, AgNO₃ and the water insoluble, and thereforeslow releasing, AgCl.

Example 2

[0176] The process of Example 1 was repeated, except that a 1.0%solution of zinc chloride was used in place of the 1.0% solution ofsodium chloride, resulting in the formation of a silver chloride colloidand zinc nitrate from half the silver nitrate in the coating solution.Zinc chloride was added in an amount of one half the amount of NaCladded in Example 1 because one mole of zinc chloride reacts with 2 molesof silver nitrate.

Example 3

[0177] The process of Example 1 was repeated, except that a 1.0%solution of copper chloride was used in place of the 1.0% solution ofsodium chloride, resulting in the formation of a silver chloride colloidand copper nitrate from half the silver nitrate in the coating solution.Copper chloride was added in an amount of one half the amount of NaCladded in Example I because one mole of copper chloride reacts with 2moles of silver nitrate.

Example 4

[0178] The process of Example 1 was repeated, except that the 1.0%solution of sodium chloride was replaced with a 1.0% solution of sodiumiodide, resulting in the formation of a silver iodide colloid and sodiumnitrate from half the silver nitrate in the coating solution. Silveriodide is a local antiinfective agent and has a lower water solubilitythan silver chloride, providing a slower releasing silver salt thansilver chloride.

Example 5

[0179] The process of Example 1 was repeated, except that the 1.0%solution of sodium chloride was replaced with a 1.0% solution sodiumpropionate, resulting in the formation of a silver propionate colloidand soluble sodium nitrate, along with the remaining silver nitrate inthe solution. Silver propionate is a local antiinfective and is morewater soluble than AgCl or AgI, providing a faster releasing salt thansilver chloride or silver iodide.

Example 6

[0180] The process of Example 1 was repeated, except that the 1.0%solution of sodium chloride was replaced with a 1.0% solution of sodiumlactate, resulting the formation of a silver lactate colloid and sodiumnitrate, along with the remaining silver nitrate in the coatingsolution. Silver lactate is a local antiinfective and is more watersoluble than sodium propionate, AgCl or AgI, providing one of thefastest releasing silver salts, other than the soluble silver nitrate.

Example 7

[0181] The process of Example 1 was repeated, except that the 1.0%solution of sodium chloride was replaced with a solution of sodiumacetate, resulting in the formation of a silver acetate colloid andsodium nitrate, along with the remaining silver nitrate in the solution.Silver acetate is a local antiinfective that is more water soluble thansodium propionate, silver chloride, or silver iodide, but less watersoluble than silver lactate.

Example 8

[0182] The process of each of Examples 1, 2, 3, 4, 5, 6, and 7 wasrepeated, except that the salt solution was added in an amountsufficient to react with 75% of the AgNO₃.

Example 9

[0183] The process of each of Examples 1, 2, 3, 4, 5, 6, and 7 wasrepeated, except that the salt solution was added in an amountsufficient to react with 100% of the AgNO₃.

Example 10

[0184] The process of each of Examples 1, 2, 3, 4, 5, 6, and 7 wasrepeated, except that the salt solution was added in an amountsufficient to react with 25% of the AgNO₃.

Example 11

[0185] The process of Example 1 was repeated, except that the NaCl saltsolution was added in an amount sufficient to react with 25% of thesilver nitrate. Then a 1.0% solution of sodium iodide was added in anamount sufficient to react with another 25% of the silver nitrate toproduce a combination of silver chloride and silver iodide colloids from50% of the silver nitrate.

Example 12

[0186] The process of Example 1 was repeated, except that the NaCl saltsolution was added in an amount sufficient to react with 25% of thesilver nitrate to produce the poorly soluble silver chloride colloid.Then a 1.0% solution of sodium propionate was added in an amountsufficient to react with another 25% of the silver nitrate to producethe slightly water soluble silver propionate colloid. Next, a 1.0%solution of sodium acetate was added in an amount sufficient to reactwith another 25% of the silver nitrate to produce the somewhat watersoluble silver acetate colloid in combination with the poorly solublesilver chloride colloid and the slightly soluble silver propionatecolloid from 75% of the silver nitrate.

Example 13

[0187] The process of Example 12 was repeated, except that an additionalamount of zinc iodide was added to convert 10% of the remaining silvernitrate to a colloid of silver iodide. This produced a coatingcontaining 15% silver nitrate, 25% of the somewhat soluble silveracetate colloid, 25% of the slightly soluble sodium propionate colloid,25% of the poorly soluble silver chloride colloid, and 10% of the verypoorly soluble silver iodide colloid, along with the soluble sodiumnitrate and zinc nitrate salt products.

[0188] As shown by the above examples, any combination of additionalsalts in any combination of different amounts can be used to convertsome or all of the soluble oligodynamic metal salts into insolublecolloidal salts within a polymer composition.

Example 14

[0189] Somewhat water soluble silver salts, such as silver lactate orsilver acetate, can be used alone or in combination with the verysoluble silver nitrate to produce other compounds that can haveantiseptic activity. For example, silver acetate at a 4:1 molar ratiowith zinc chloride produces 50% silver chloride colloid and the zincacetate counter salt, which is also an antiseptic, and leaves 50%unreactive silver acetate. Similarly, other silver salts can be usedalone or in combination to produce multiple counter salts that haveantiseptic or other desirable activity.

[0190] For example, the process of Example 2 was repeated except that asoluble combination of silver nitrate, silver acetate, and silverlactate was used in place of the 10% silver nitrate solution. When thezinc chloride is added, a colloid of silver chloride is formed in thepolymer composition and the soluble counter salts zinc nitrate, zincacetate, and zinc lactate are produced. The zinc acetate and zinclactate provide antiseptic activity in addition to the antimicrobialactivity of the silver salts. In this example any metal salt other thanzinc chloride which produces counter salts with the nitrate, acetate,and lactate that have a desired effect, such as antiseptic orantimicrobial activity, can be used. An example of such a salt is copperchloride.

[0191] Different oligodynamic salts have different water solubilities.This allows for tailoring of the composition to provide a specificrelease profile of the antimicrobial agent(s) from the composition. Forexample, sodium chloride, zinc iodide, sodium citrate, sodium acetate,and sodium lactate can be added to a coating composition containingsilver nitrate to produce a coating which contains the water solublesalts silver nitrate and zinc nitrate, the somewhat water soluble saltssilver lactate (67 mg/ml water) and silver acetate (10 mg/ml water), theslightly soluble salt silver citrate (0.3 mg/ml water), the poorlysoluble salt silver chloride (0.002 mg/ml water), and the very poorlysoluble salt silver iodide (0.00003 mg/ml water). By adjusting theproportions of salts having different solubilities in the composition,the release rate of the active oligodynamic agent(s) can be altered toprovide a shorter or longer release profile over time.

[0192] For example, the process of Example 1 was repeated, except thatin addition to the NaCl salt solution, 1% solutions of zinc iodide,sodium citrate, sodium acetate and sodium lactate were added, each in anamount sufficient to react with 15% of the silver nitrate, to producecolloids of silver chloride, silver iodide, silver citrate, silveracetate, and silver lactate in the final coating composition, along with25% unreacted silver nitrate, and the silver nitrate and zinc nitratesalt products. The difference in solubility of the different silversalts will produce different and prolonged rates of silver ion releasein the coating when exposed to body fluid.

Example 15

[0193] To form the coating composition for PVC catheters, a 3.3%solution of a polyether polyurethane-urea block copolymer available fromCardioTech International, Inc. was prepared in THF. A 3.3% solution ofPolyvinyl chloride (PVC) was then prepared in methylene chloride. Thetwo solutions were then combined in equal amounts to provide a 50/50ratio by weight of the two polymers in solution. A sufficient quantityof 10% silver nitrate (AgNO₃) solution in alcohol was then added to thepolyurethane-urea/PVC polymer solution to produce a final silverconcentration of approximately 5%, based on coating solids in thesolution. A 1% zinc chloride solution in a 75/25 mixture by weight ofethanol/water was added to the coating solution in an amount sufficientto react with 50% of the AgNO₃ to produce a colloid of the poorly watersoluble salt AgCl from half of the AgNO₃. The ZnCl₂ solution was addedslowly to the polymer solution with stirring, and the solution began toturn cloudy with the formation of the fine colloidal AgCl. The amount ofwater in the final coating solution was slightly less than about 1% ofthe total solvent weight. A PVC endotracheal tube was then coated bydipping it into the coating composition, followed by drying usingstandard methods. The finished coating contained both the water soluble,and therefore fast releasing, AgNO₃ and the poorly water soluble, andtherefore slow releasing, AgCl.

Example 16 Dog Intubation Study

[0194] Twelve adult mongrel dogs were orally intubated. Dogs wererandomly assigned to be orally intubated either with an endotrachealtube with a coating of the present invention or a noncoated endotrachealtube. The animal care providers were blinded to the animals' study groupassignments and all interpretation of the microbiology data andhistology data were performed by blinded observers. The animals wereassigned to their study groups using a random-number generator. Cuffedendotracheal tubes (Intermediate Hi-Lo, 7.5 mm internal diameter,Mallinckrodt Medical, St. Louis, Mo.) were used for the control animals.For the test animals, the inner and outer surfaces of identicalendotracheal tubes were coated with a coating of the present invention.

[0195] The test coating was composed of a polymer blend that was 50%polyvinyl chloride (PVC) and 50% polyurethane. The coating had a silvercontent on the device surface of 3.3 micrograms/cm². The silver was acolloid of silver chloride that had been prepared by combining sodiumchloride with silver nitrate in a polymer solution. The tubes for thecontrol and test groups were repackaged and sterilized with ethyleneoxide.

[0196] Twelve mongrel adult dogs (17 to 31 kg; Levon Thalen; Strathmore,AB, Canada) were used in the study. Six animals were assigned to receivethe coated endotracheal tubes, while six animals received standardnoncoated endotracheal tubes. All animals were healthy and free ofdisease prior to the initiation of the study. Animals that had receivedany antibiotics <1 week prior to the study were excluded.

[0197] The animals were anesthetized with a single injection of sodiumpentobarbital (30 mg/kg) and were maintained in a state of anesthesia byproviding sodium pentobarbital at approximately 1 mg/kg/h. They wereplaced in the dorsal recumbent position for the duration of themechanical ventilation proposed in the study protocol (i.e., up to 4days of mechanical ventilation). Animals were provided lactated Ringerssolution at a rate of 100 mL/h, and urinary catheters were placed toprovide urinary drainage. Following tracheal intubation, animals wereplaced on a ventilator (Harvard Biosciences; South Natick, Mass.) set todeliver 350 to 500 mL tidal volume of room air (50% relative humidity)at a rate of 15 to 20 breaths/min. The tidal volume delivered to theanimals was selected and maintained to provide peak airway pressures of<30 cm H₂O throughout the duration of mechanical ventilation. Allanimals received a level of positive end expiratory pressure of 5 cmH₂O.

[0198] Prior to the bacterial challenge, blood and buccal culturesamples were taken from each animal. After sedation and trachealintubation, each animal was challenged twice (at 1 and 8 hours (h) afterthe tracheal intubation) with a respiratory isolate of Pseudomonasaeruginosa (strain PAO1). For each challenge, 5 mL of approximately 10⁷cfu/mL of a log-phase culture of P. aeruginosa was instilled into thebuccal pouch of the animals. The animals were positioned with theirheads turned so that any excess fluid drained out from the mouth, ratherthan down into the pharynx.

[0199] Buccal culture samples were taken every 24 hours after intubationand were plated quantitatively on both nutrient agar and P. aeruginosaisolation agar to identify the total amount of aerobic bacteria and thechallenge bacteria. Using sterile suctioning tubes and mucous specimentraps, animals were suctioned via the inner lumen of their endotrachealtubes three times per day to remove secretions. However, a minimalamount of recovered tracheal aspirate hindered any attempt toquantitatively assess the bacterial burden from these samples. Rather,the presence of bacteria within the endotracheal tubes was assessed bydaily sampling of the endotracheal tube lumens with a cotton cultureswab.

[0200] Body temperature was monitored continuously and was recordedthree times daily to determine the presence of fever in the animals.Blood samples were taken daily from each animal and were cultured usingan automated blood culture system (Bactec NR 860; Becton-Dickinson;Franklin Lakes, N.J.). The bacteria were identified as P. aeruginosa,other pathogenic aerobic bacteria, or contaminants, using standardmicrobiological methods.

[0201] Animals were sacrificed by an overdose of sodium pentobarbitalafter receiving 96 hours of mechanical ventilation. Postmortemexaminations were conducted within 4 to 6 hours of death for all animalsusing criteria that were determined prospectively in the study protocol.Any indwelling devices (e.g., IV catheter or urinary catheter) werecultured. Gross postmortem examinations were conducted on each dog. Theendotracheal tube was removed by dissection, rather than by being pulledout, to prevent the removal of adherent bacteria and secretions. Thelungs and the trachea were removed from each animal and weighed.

[0202] The gross lung appearance was recorded and scored according tothe following scheme: 0, normal; 1, hyperemia, edema, and congestioninvolving <10% of examined lungs; 2, hyperemia, edema, and congestioninvolving 10 to 29% of the lungs; 3, hyperemia, edema, and congestioninvolving 30 to 60% of the lungs; and 4, hyperemia, edema, andcongestion involving >60% of the lungs.

[0203] The gross appearance of the endotracheal tube also was assessedusing the following scheme: 0, no mucus or purulent material on thesurface of the endotracheal tube; 1, mucus covering <10% of theendotracheal tube length and <10% obstruction of the endotracheal tubelumen; 2, mucus or purulent material covering or obstructing 10 to 25%of the endotracheal tube surface and/or lumen; 3, mucus covering orobstructing 25 to 50% of the endotracheal tube surface and/or lumen; and4, mucus covering or obstructing >50% of the surface and/or lumen of theendotracheal tube.

[0204] Tissue samples from each identified primary lung lobe werecollected for quantitative cultures (i.e., total bacteria and P.aeruginosa) and histologic examination. As all animals were placed inthe dorsal recumbent position, the diaphragmatic lobes (caudal lobes)were determined to be in a dependent position. Additionally, samplesfrom the mid-portions of the two mainstem bronchi and the trachea (i.e.,proximal trachea [i.e., upper third of the trachea], middle trachea[i.e., just above the cuff of the endotracheal tube], and distal trachea[i.e., tracheal surface in contact with the cuff of the endotrachealtube]) were collected for quantitative microbiology.

[0205] Cultures from the inner lumen surface of the endotracheal tubewere collected at the postmortem examination from three 1-cm segments ofthe tube. The three samples were taken from the proximal third of theendotracheal tube, from the portion of the tube just proximal to thecuff, and from the cuffed portion of the endotracheal tube. The innerlumen surface from the cut pieces of the endotracheal tubes were swabbedwith cotton-tipped applicators to identify the bacteria. The applicatorsthen were sonicated and plated onto the appropriate medium to enumeratethe amount of total bacteria as well as that of P. aeruginosa.

[0206] Microbiology

[0207] For each tested tissue sample, a weighed, aseptically preparedtissue portion was homogenized in sterile phosphate-buffered salinesolution (5 mL). This was serially diluted, and 100 μl was spread-platedonto nutrient agar and P. aeruginosa isolation agar to obtainquantitative cultures using techniques described in: Baselski VS, et al.“The standardization of criteria for processing and interpretinglaboratory specimens in patients with suspected ventilator-associatedpneumonia.” Chest 1992; 102[suppl]:571S-579S.

[0208] Histologic Interpretation

[0209] All microscopic samples were scored based on the grading scaledescribed below by an animal pathologist (MEO) and were scoredindependently by a second animal pathologist (BGH). Both pathologistswere blinded to the experimental protocol and the region of sampling.The histologic classification of lung tissue specimens was similar tothat employed by other investigators (Baron et al. “Classification andidentification of bacteria.” In: Murray PR, ed. Manual of clinicalmicrobiology. Washington, D.C.: ASM Press, 1995; 249-264; Marquette, etal. “Characterization of an animal model of ventilator-acquiredpneumonia.” Chest 1999; 115:200-209). Fresh tissue samples were fixed in10% neutral buffered formalin. After fixation for >24 h, samples weredehydrated in ethanol and xylene and were embedded in paraffin. Aftersectioning, tissue samples were stained with hematoxylin-eosin. Sectionswere examined and photographed on a light microscope (Nikon; Tokyo,Japan), after which each photograph was assigned a unique and permanentidentification number.

[0210] Histology samples of the lung were scored using several scales.

[0211] Hyperemia: 0, no hyperemia; 1, (slight) capillaries distendedwith blood; 2, (moderate) capillaries distended with blood and somealveoli filled with serous fluid and/or blood; and 3, (severe)capillaries are distended with blood and most alveoli are filled withserous fluid and/or blood.

[0212] Edema: 0, no edema; 1, slight interstitial fluid accumulation; 2,serous fluid in alveoli and moderate interstitial fluid accumulation;and 3, large amounts of serous fluid in alveoli and excessiveinterstitial fluid accumulation.

[0213] Cellular infiltration: 0, no cellular infiltration into alveolaror interstitial space; 1, occasional neutrophils; lymphocytes and/orlarge mononuclear cells in the alveoli and interstitial space associatedwith some alveoli; 2, moderate numbers of neutrophils, lymphocytes, andlarge mononuclear cells in the alveoli and interstitial space associatedwith most alveoli; and 3, large numbers of neutrophils, lymphocytes, andlarge mononuclear cells in the alveoli and interstitial space of mostalveoli.

[0214] Bacteria: 0, no bacteria visible; 1, occasional bacteria evidentwithin phagocyte; 2, bacteria within most phagocytes and occasional freebacteria; and 3, large numbers of bacteria present within phagocytes andwithin the alveolar and interstitial spaces.

[0215] Data were reported as the mean ±SD. All primary comparisonsbetween the test and control animals were based on the data for eachlobe, unless otherwise noted. The Fisher's Exact Test was used tocompare categoric data, and the Mann-Whitney test was used to comparenon-normal, continuous data. The Spearman rank test was used tocorrelate histologic and microbiology data for each lobe. The Kstatistic was used to assess the interobserver agreement for lunginfiltration with neutrophils.

[0216] Intubation was performed without difficulty and was achieved onthe first attempt for all animals. Six of the animals that had receivednoncoated endotracheal tubes and five that had received silver-coatedtubes completed the study protocol and were included in the dataanalysis. One animal receiving a silver-coated endotracheal tube died 6h after intubation. This animal mistakenly received an initial tidalvolume of >500 mL, resulting in pneumothorax and subsequent death by anoverdose of sodium pentobarbital. The lungs appeared normal at necropsy,and this animal was not included in the data analysis as it did notreceive the bacterial challenge with P. aeruginosa. There was nostatistical difference in the duration of mechanical ventilation and theday of death for dogs receiving either the noncoated or thesilver-coated endotracheal tubes (3.0±1.5 vs. 3.6±0.5 days,respectively; p=0.330). Three of five animals (60.0%) that had beentreated with silver-coated endotracheal tubes survived to the end of thestudy period at 96 h compared to three of the six control animals(50.0%; p>0.999). The cause of death for the dogs receivingsilver-coated endotracheal tubes included euthanasia for the three dogscompleting the protocol, and cardiac arrest and renal failure for thetwo dogs not completing the study protocol, which were expectedcomplications among mechanically ventilated dogs. The cause of death forthe dogs receiving noncoated endotracheal tubes included euthanasia forthe three dogs completing the protocol, septic shock from P. aeruginosabacteremia in two animals, and excessive purulent secretions resultingin endotracheal tube occlusion in one animal.

[0217] Buccal Cultures: For both test and control dogs, theconcentration of P. aeruginosa in the buccal secretions increased within24 h after anesthesia administration and inoculation to >10⁸ cfu/gaspirate. No statistical differences were seen between the two groupsfor the degree of buccal colonization throughout the duration of thestudy period.

[0218] Endotracheal Tube Lumen Cultures: The average time untilcolonization with P. aeruginosa of the inner lumens of the noncoated andsilver-coated endotracheal tubes was 1.8±0.4 and 3.2±0.8 days,respectively (p=0.016). On day 2 of mechanical ventilation, the innerlumens of six of six (100.0%) noncoated endotracheal tubes werecolonized by aerobic bacteria and 1 of 5 (20.0%) silver-coatedendotracheal tubes were colonized with aerobic bacteria (p =0.015).Three of six noncoated endotracheal tubes (50.0%) and one of fivesilver-coated endotracheal tubes (20.0%) were colonized with P.aeruginosa on day 2 of mechanical ventilation (p=0.546). FIG. 2 showsthe cumulative probability of the endotracheal tubes having culturesnegative for P. aeruginosa or aerobic bacteria for the 3 days followingintubation and inoculation of the dogs.

[0219] The concentration of aerobic bacteria from the sampled innerlumen segments of the endotracheal tubes at the time of necropsy wasgreater than that for the noncoated endotracheal tubes compared to thesilver-coated endotracheal tubes (6.1±1.3 vs. 4.1±2.1 log cfu/cm,respectively; p=0.009). Similarly, the concentration of P. aeruginosafrom the sampled inner lumen segments of the endotracheal tubes wasgreater for the noncoated endotracheal tubes (4.1±1.0 vs. 2.6±1.9 logcfu/cm, respectively; p=0.076).

[0220] Tracheal and Bronchial Cultures: The trachea and mainstem bronchiwere heavily colonized with P. aeruginosa at postmortem examination. Theupper, mid-portion, and distal trachea, and the mainstem bronchi weremore heavily colonized with P. aeruginosa, and all aerobic bacteria,among dogs receiving noncoated endotracheal tubes compared to dogsreceiving silver-coated endotracheal tubes (Table 1). However, thesedifferences did not reach statistical significance. TABLE 1 BacterialCounts in the Trachea and Mainstem Bronchi* P aeruginosa All AerobicBacteria Dogs Dogs Dogs receiving Dogs receiving receiving Silver-receiving Silver- Noncoated Coated Noncoated Coated EndotrachealEndotracheal p Endotracheal Endotracheal P Location Tubes (n = 6) Tubes(n = 5) Value Tubes (n = 6) Tubes (n = 5) Value Proximal 6.2 ± 0.8 5.5 ±0.7 0.234 6.9 ± 0.6 6.1 ± 0.5 0.083 trachea Mid- 5.8 ± 0.6 5.3 ± 0.70.272 7.1 ± 0.9 6.4 ± 0.8 0.315 trachea Distal 5.8 ± 0.7 4.8 ± 0.8 0.0546.7 ± 0.8 6.3 ± 1.2 0.647 trachea Mainstem 4.4 ± 2.4 3.6 ± 2.0 0.111 5.6± 1.0 4.5 ± 1.0 0.054 bronchi

[0221] Lung Parenchymal Cultures: Bacteria were cultured from all lungtissue samples that were taken at necropsy. The total aerobic bacterialburden in the lung parenchyma was statistically lower among the dogsthat had received the silver-coated endotracheal tubes (4.8±0.8 vs.5.4±0.9 log cfu/g lung tissue, respectively; p=0.010) (Shown in FIG. 3).The tissue concentration of P. aeruginosa among dogs in thesilver-coated group was also lower compared to dogs in the noncoatedendotracheal tube group (4.3±1.2 vs. 4.4±2.1 log cfu/g lung tissue,respectively; p=0.055). The achieved thresholds of P. aeruginosa amongthe 36 lung lobes from dogs receiving noncoated endotracheal tubes were29 (80.6%) with ≧10⁴ cfu/g, 19 (52.8%) with ≧10⁵ cfu/g, and 6 (16.7%)with ≧10⁶ cfu/g, compared to 20 (66.7%) with ≧10⁴ cfu/g, 7 (23.3%) with≧10⁵ cfu/g, and 3 (10.0%) with ≧10⁶ cfu/g among the 30 lung lobes fromdogs receiving silver-coated endotracheal tubes (p=0.105). The achievedaerobic bacterial thresholds among the 36 lung lobes from dogs receivingnoncoated endotracheal tubes were 34 (94.4%) with 10⁴ cfu/g, 24 (66.7%)with ≧10⁵ cfu/g, and 13 (36.1%) with ≧10⁶ cfu/g, compared to 25 (83.3%)with 10⁴ cfu/g, 9 (30.0%) with ≧10⁵ cfu/g, and 4 (13.3%) with ≧10⁶ cfu/gamong the 30 lobes from dogs receiving silver-coated endotracheal tubes(p=0.028).

[0222] Blood Cultures: Bacteria blood cultures were seen in three of six(50.0%) control animals and in one of the five animals receivingsilver-coated endotracheal tubes. P aeruginosa bacteremia was seen intwo of six control animals and in zero of five test animals.Staphylococcus aureus was isolated from the blood of one dog receiving anoncoated endotracheal tubes and in one dog receiving a silver-coatedendotracheal tube. For the three control animals, the positive bloodcultures were found on days 2, 3, and 4. The positive blood culture wasseen in the test animal on day 4.

[0223] Postmortem Examination

[0224] Endotracheal Tubes Gross Appearance: Five of six of the noncoatedendotracheal tubes (83.3%) and zero of five of the silver-coatedendotracheal tubes (0.0%) had at least a 50.0% narrowing of their lumensdue to the presence of mucus at necropsy (p=0.015). The mean grossappearance score for the noncoated endotracheal tubes was statisticallygreater than for the silver-coated endotracheal tubes (3.6±1.2 vs.1.2±0.8, respectively; p=0.030).

[0225] Lungs: There was no statistical difference in the mean weight ofthe lungs for the animals receiving the noncoated and silver-coatedendotracheal tubes (634±130 vs. 592±53 g, respectively; p=0.524). Themean scores for the gross appearance of the entire lung for the dogsreceiving noncoated and silver-coated endotracheal tubes were 3.2±1.2and 1.2±0.4, respectively (p=0.030). The major pathologic findings werecongestion and hyperemia in both groups. Both veterinary pathologistsfound statistically significant differences in the histologic evaluationof the dogs receiving noncoated endotracheal tubes compared to the dogsreceiving silver coated endotracheal tubes (MEO: 7.1±1.6 vs. 2.8±1.2,respectively [p<0.001]; BGH: 3.0±0.7 vs. 2.1±1.3, respectively[p=0.001]). FIG. 4 depicts a scatter plot of histology scores (x-axis)plotted against the lung tissue concentration of total aerobic bacteria(y-axis). The regression line is also shown.

[0226] The most prominent histologic changes consisted of diffuseneutrophil infiltration into the alveolar walls and capillaries, whichwas noted primarily in the dogs receiving noncoated endotracheal tubes.One observer (BGH) noted that 21 of 33 lung lobes (63.6%) from dogsreceiving noncoated endotracheal had large numbers of interstitialneutrophils present compared to only 1 of 28 lung lobes (3.6%) from dogsreceiving silver-coated endotracheal tubes (p<0.001). Similarly, thesecond observer (MEO) scored 17 of 33 lung lobes (51.5%) and none of 28lung lobes (0.0%) from the same groups of animals, respectively, ashaving large numbers of interstitial neutrophils (p<0.001). The κstatistic for agreement between these two observers was 0.3642 (p=0.005)for scoring neutrophil infiltration in the alveolar walls andcapillaries.

[0227] Correlation of Microbiological and Histologic Findings: Astatistically significant correlation was found between theconcentration of aerobic bacteria in the lung tissue specimens and theobserved histology scores (Spearman rank correlation coefficient, 0.430;p<0.001, see FIG. 3). Similarly, a statistically significant correlationwas found between the concentration of P. aeruginosa in the lung tissuespecimens and the observed histology scores (Spearman rank correlationcoefficient, 0.356; p=0.005).

Example 17 Rabbit Study

[0228] A study was conducted in rabbits to assess whether silver-coatedendotracheal tubes reduce the colonization and migration of a bacteriachallenge as compared to non-coated tubes. Observations were also maderegarding the biocompatibility of the silver-coated device.

[0229] 12 adult female New Zealand White rabbits were anesthetized andintubated with 3 mm inner diameter (ID) endotracheal tubes. Six rabbitsreceived endotracheal tubes (referred to throughout this application asETTs or ET tubes) coated with a polymer coating in which the polymer was50% PVC and 50% polyurethane. The coating contained 5% colloidal silverchloride by weight. (The tubes were coated using procedures essentiallyidentical to those of EXAMPLE 25). Six additional rabbits served as acontrol group and received ETTs that were identical to these tubesexcept that they were not coated. The tube's exterior within the oralcavity of the rabbits was inoculated at 0 and 6 hours with a respiratoryP. aeruginosa isolate (PAO1, 1 ml each time, 9×10⁹ CFU/ml in a salinesolution). Subjects were positions to prevent the inocula from drainingdown the tube. The animals were maintained under anesthesia for 16 hourswithout incident and sacrificed. The endotracheal tube and adjacenttrachea distal to the larynx were aseptically removed by dissection.Samples of the proximal (ventilator end), middle, and distal (patientend) portions from both the endotracheal tubes and tracheal tissue andwere taken for quantitative microbiology (total aerobic bacteria and P.aeruginosa).

[0230] The proximal 1 centimeter, middle 1 cm, and distal 1 cm of thetrachea in contact with the endotracheal tube for each animal wereremoved and placed in 1 ml of phosphate buffered saline. These sampleswere sonicated for 5 minutes then diluted 10-fold in PBS. The solutionswere plated on tryptic soy agar and Pseudomonas isolation agar.

[0231] The proximal 1 centimeter, middle 1 cm, and distal 1 cm of eachendotracheal tube were removed and placed in 1 ml of phosphate bufferedsaline. The lumen of the tube was disinfected with a 70% alcohol soakedswab. These samples were sonicated for 5 minutes then 10-fold diluted inPBS. The solutions were plated on tryptic soy agar and Pseudomonasisolation agar.

[0232] A lung sample from each animal was collected in a pre-weighedvial containing 1 ml of phosphate buffered saline. The samples weresonicated for 5 minutes then 10-fold diluted in PBS. The solutions wereplated on tryptic soy agar and Pseudomonas isolation agar.

[0233] Samples of trachea and endotracheal tube were also collected forvisualization under a scanning electron microscope.

[0234] Bacterial burden was determined by manual plate count. Bacterialburden on the proximal, middle, and distal samples from the tubes andtrachea were found to be not statistically different by the F test foranalysis of variance. Accordingly, the proximal, medial, and distalsamples were grouped for subsequent analysis. The histopathology oftracheal samples was also assessed.

[0235] For P. aeruginosa , 6/6 of the control tubes were colonizedcompared to 2/6 of the silver-coated tubes. As well, 6/6 of the controlrabbits' tracheal tissues were colonized compared to 3/6 of the testrabbits. P. aeruginosa had migrated to the lung tissue of 4/6 controlrabbits, but no (0/6) test rabbits showed P. aeruginosa in the lungs.Histopathology of the control rabbit tracheas consistently demonstratedlarge numbers of inflammatory cells (polymorphonuclear leukocytes orPMNs) and blunted cilia. For the test rabbits, only one rabbit wascharacterized by having large numbers of inflammatory cells (PMNs), tworabbits had PMNs with intact epithelium, and three rabbits werecharacterized as having normal tissue. Histopathology observationsappear in Table 2. Bacteria counts appear in Tables 3 and 4. TABLE 2Histopathology of tracheal samples removed from rabbits Rabbit IDHistopathology Description  1 Large numbers of inflammatory cells(PMN's) within the lumen of the Uncoated trachea. Inflammatory cellspresent between the ciliated columnar epithelial cells and in thesubmucosal space. Cilia are blunt and in some cases sparse.  2Inflammatory cells (PMN's) within the lumen of the trachea. UncoatedInflammatory cells present between the ciliated columnar epithelialcells and in the submucosal space. Cilia are blunt and in some casessparse.  3 Large numbers of inflammatory cells (PMN's) within the lumenof the Uncoated trachea. Inflammatory cells present between the ciliatedcolumnar epithelial cells and in the submucosal space. Some trachealareas denuded of epithelial cells. Cilia are blunt and in some casesparse.  4 Large numbers of inflammatory cells (PMN's) within the lumenof the Uncoated trachea. Inflammatory cells present between the ciliatedcolumnar epithelial cells and in the submucosal space. Many trachealerosions are evident and there is extensive PMN infiltration at thesesites. Cilia are blunt and in some cases sparse.  5 Large numbers ofinflammatory cells (PMN's) within the lumen of the Uncoated trachea.Inflammatory cells present between the ciliated columnar epithelialcells and in the submucosal space. Many tracheal erosions are evidentand there is extensive PMN infiltration at these sties. Cilia are bluntand in some cases sparse.  6 Large numbers of inflammatory cells (PMN's)within the lumen of the Uncoated trachea. Much of the epithelial liningis absent Inflammatory cells present in the submucosal space. Manytracheal erosions are evident and there is extensive PMN infiltration atthese sites. Cilia are blunt and In some cases sparse  7 Inflammatorycells (PMN's) within the lumen of the trachea. Epithelial Coated liningis intact and there are no erosions. Occasional inflammatory cellspresent in the submucosal space. Cilia are blunt and in some casesparse.  8 Inflammatory cells (PMN's) within the lumen of the trachea.Epithelial Coated lining is intact and there are no erosions. Occasionalinflammatory cells present in the submucosal space. Cilia are blunt andin some case sparse.  9 The tissue appears normal. Coated 10 The tissueappears in general normal. Occasional Inflammatory cells Coated (PMN's)within the lumen of the trachea. 11 The tissue appears normal. Coated 12Large numbers of inflammatory cells (PMN's) within the lumen of theCoated trachea. Much of the epithelial lining is absent. Inflammatorycells present in the submucosal space. Many tracheal erosions areevident and there is extensive PMN infiltration at these sites. Ciliaare blunt and in some cases sparse

[0236] TABLE 3 Total bacterial Counts on Endotracheal Tube, Trachea andLung Total Bacterial Count (TSA) Endotracheal Tube (cfu/cm) Trachea(cfu/cm) Rabbit Proximal Mid Distal Proximal Mid Distal Lung (cfu/g)  1(control) 3.0e6 1.9e6 8.0e5 1.7e5 1.0e5 7.0e5 4.0e5  2 (control) 1.8e41.9e4 3.4e5 3.5e4 2.1e4 1.4e4 5.8e5  3 (control) 1.9e4 4.0e4 4.4e4 1.0e66.0e5 5.5e5 4.5e5  4 (control) 2.4e5 2.9e5 1.2e6 4.4e5 7.3e4 6.0e4 1.0e5 5 (control) 6.4e5 6.6e5 1.9e6 6.2e5 3.0e4 3.1e4 2.9e5  6 (control)4.0e4 2.5e6 2.5e5 1.5e5 2.4e4 1.4e5 NG  7 (test) 1.4c3 2.0e4 1.9e3 6.0e27.9e3 2.4e2 NG  8 (test) 1.3e2 NG NG 1.9e3 2.2e3 1.4e2 NG  9 (test) NGNG NG NG NG NG NG 10 (test) 8.0e3 7.5e4 2.2e4 1.7e5 1.0e5 3.0e5 NG 11(test) NG NG NG NG NG NG NG 12 (test) 5.0e2 7.5e2 3.5e3 2.0e3 1.1e59.0e5 NG

[0237] TABLE 4 Pseudomonas Counts on Endotracheal Tube, Trachea and LungPseudomonas Count (PIA) Endotracheal Tube (cfu/cm) Trachea (cfu/cm)Rabbit Proximal Mid Distal Proximal Mid Distal Lung (cfu/g)  1 (control)1.0e5 7.0e5 6.6e5 4.0e4 5.0e4 1.1e4 2.0e3  2 (control) 3.9e2 4.4e3 7.2e33.1e4 4.5e3 1.2e4 NG  3 (control) 1.0e3 6.0e3 4.2e3 1.9e3 1.1e3 9.4e21.6e3  4 (control) 1.0e3 2.4e3 5.5e4 4.0e4 3.3e4 6.7e3 5.6c3  5(control) 2.7e3 3.6e4 3.0e4 4.2e3 7.7e3 1.1e2 4.3e4  6 (control) NG5.0e4 5.0e3 1.5e3 6.5e3 3.8e4 NG  7 (test) 7.0e2 1.1e2 2.0e2 1.0e2 3.5e25.5e2 NG  8 (test) NG NG NG NG NG NG NG  9 (test) NG NG NG NG NG NG NG10 (test) 3.1e3 2.4e4 8.5e3 4.5e4 2.5e4 4.5e4 NG 11 (test) NG NG NG NGNG NG NG 12 (test) NG NG NG 2.5e2 2.0e2 1.0e2 NG

[0238] Numbers are presented in exponential notation. For example,“5.0e2” refers to 5×10².

[0239] Table 5 summarizes the quantitative microbiological findings forwhich log₁₀ reductions of 2-4 were measured for the groups receiving thesilver-coated ETTs. TABLE 5 Aerobic Bacteria^(a) Pseudomonas^(a) ETTTrachea Lung ETT Trachea Lung Non-coated 5.42 ± 0.78 5.08 ± 0.61 4.58 ±2.26 3.84 ± 1.33 3.83 ± 0.72 2.48 ± 1.99 Silver- 1.95 ± 1.90 2.66 ± 2.200.54 ± 1.32 1.05 ± 1.62 1.54 ± 1.77 0.00 ± 0.00 coated p Values^(b)<0.0001 0.0010 0.0167 <0.0001 0.0004 0.0208

Example 18 In Vitro Microbial Adherence Studies

[0240] Microbial adherence assays were performed on coated tubes withdifferent silver levels and adherence was compared to a non-coated PVCET tube. The coating was a polymer composition of 50% PVC and 50%polyurethane with silver present as colloidal silver chloride (preparedfrom silver nitrate and sodium chloride). The first step in devicecolonization is adherence of organisms to the surface, and this stepoccurs in a relatively short time (minutes). The assay assessesmicrobial adherence relative to a non-coated control by exposingportions of the tubes to high concentrations of various organisms(10⁸-10⁹ CFU/ml) for 2 hours. An alternative procedure is used forCandida because their adherence occurs slowly and with few organisms.Coated samples of known size are prepared from coated endotracheal tubesand compared with uncoated controls.

[0241] Procedure for Organisms Other Than Candida

[0242] Cultures were prepared for each organism as follows. 200 ml ofsterile media was inoculated with bacteria from a starter culture.Bacteria were then grown in Trypticase Soy Broth at 37±1° C. on a rotaryshaker (approximately 150 rpm) for 12-18 hours. Cells were harvested bycentrifugation for approximately 10 minutes at 4000×g at approximately25° C., then washed twice using approximately 30 ml of 0.9% saline andcentrifugation as described above.

[0243] Cells were suspended in minimal broth and adjusted to an opticaldensity at 600 nm corresponding to a cell density of approximately 2×10⁸cells/ml. This suspension was then incubated at 37±1° C. with rotaryshaking (approximately 150 rpm) for 1 hour ±10 minutes. L-[3, 4, 5⁻³H]-leucine was then added at a volume of 0.05% of the volume of the cellsuspension (e.g., 20 μl leucine would be added to 40 ml of cellsuspension). Incubation was continued for an additional 20±5 minutes.Cells were harvested and washed twice using approximately 30 ml of 0.9%saline and centrifugation at 4000×g at approximately 25° C. The pelletwas then suspended in 0.9% PBS to a final concentration of approximately10⁸ cells/ml.

[0244] Samples (coated and uncoated) were incubated with rotary shaking(˜150 rpm) for 2 hours in the radiolabeled cell suspension at 37±2° C.The volume of cell suspension completely covered the sample. At the endof incubation, samples were immersed five times (approximately 1 secondeach time) in each of three successive volumes (approximately 160 ml) of0.9% saline. Excess saline was then shaken from each piece and sampleswere placed in separate 20 ml glass scintillation vials containing 10 mlOpti-Fluor7 scintillation cocktail (Packard Instrument Co.). DPM wasmeasured in each vial using a liquid scintillation counter (LS-5801,Beckman Instruments).

[0245] The number of organisms, as colony-forming units (CFU),corresponding to the radioactivity (DPM) was determined by seriallydiluting and plating labeled organisms and determining the radioactivityof the sample in DPM. A calibration chart was first prepared bymeasuring the DPM of samples containing a known number of radiolabeledCFU. The calibration chart was then used to convert DPM measurements toCFU. Microbial adherence is reported below for all samples (other thanCandida spp.) as CFU per surface area of the device sample (CFU/mm²).Within each testing batch, the coated samples are compared to thenon-coated samples, and a percent reduction in adherence is determined.

[0246] Procedure Used for Candida spp.

[0247] Cultures were prepared for Candida species as follows. 200 ml ofsterile media was inoculated with cells from a starter culture. Cellswere then grown in Sabouraud Dextrose Broth (SDB) at 25±1° C. in arotary shaker (approximately 150 rpm) for 24 hours. Cells were harvestedby centrifugation for approximately 10 minutes at 4000×g atapproximately 25° C., then washed twice using approximately 30 ml of0.9% saline and centrifugation as described above.

[0248] Test samples were prepared for each suspension by cutting piecesof the tube. Samples were incubated with rotary shaking (˜150 rpm) for18 hours in the cell suspension at 37±2° C. The volume of cellsuspension was sufficient to completely cover the sample. At the end ofincubation, samples were removed and immersed five times (approximately1 second each time) in each of three successive volumes (approximately160 ml) of 0.9% saline. Excess saline was shaken from each piece and therinsed test samples were each transferred into corresponding vials ofPBS containing L-[3, 4, 5- ³H]-leucine at a volume of 0.05% of the totalmedia volume and incubated at 37±1° C. with rotary shaking(approximately 150 rpm) for 30±5 minutes.

[0249] At the end of incubation, each test piece was immersed five times(approximately 1 second each time) in each of three successive volumes(approximately 160 ml) of 0.9% Saline. Excess saline was shaken fromeach piece and each piece was placed in separate 20 ml glassscintillation vials containing 10 ml Opti-Fluor7 scintillation cocktail(Packard Instrument Co.). DPM was measured in each vial with a liquidscintillation counter, (LS-5801, Beckman Instruments). Data wascorrected for background decay. For Candida, adherence values are inscintillation units of DPM, rather than CFU.

[0250] Microorganisms relevant to the study of respiratory infectionswere used in the assay. Clinical isolates from airway and sputum samplesfrom hospital laboratories and American Type Culture Collection (ATCC)were used. Greater differences in adherence were seen in organisms thatadhere in greater numbers. Table 6 below summarizes the results. TABLE 6Summary of In Vitro Microbial Adherence Studies Score Comparison toNon-Coated ETT 2 Statistically less adherence on Silver-Coated ETT, >90%reduction 1 Statistically less adherence on Silver-Coated ETT, >range30%-90% reduction 0 Statistically equivalent adherence −1 Statisticallygreater adherence to Silver-Coated ETTs

[0251] Performance Non-coated Silver^(a) Silver^(a) Silver^(a) OrganismID# CFU/mm² 5.5 μg/cm² 13.0 μg/cm² 20.4 μg/cm² Pseudomonas aeruginosaATCC 27853 3.91 × 10⁵ 2 2 2 Pseudomonas aeruginosa NGH 52461-02 3.62 ×10⁵ 2 2 2 Pseudomonas aeruginosa ATCC 27318 2.36 × 10⁵ 2 2 2 Pseudomonasaeruginosa GSU-3 1.39 × 10⁵ 2 2 2 Pseudomonas aeruginosa ATCC 17831 1.38× 10⁵ 2 2 2 MRSA U Cinn 4.05 × 10⁴ 1 1 1 Enterobacter cloacae U Cinn1.93 × 10⁴ 1 1 1 Enterobacter aerogenes ATCC 13048 1.50 × 10⁴ 1 1 1Staphylococcus aureus ATCC 700698 1.34 × 10⁴ 1 1 1 Klebsiella pneumoniaeATCC 8047 1.13 × 10⁴ 1 0 1 Enterobacter aerogenes U Cinn 9.06 × 10³ 1 11 Acinetobacter baumannii U Cinn 5.29 × 10³ 1 0 0 Klebsiella pneumoniaeNGH 52461-03 3.18 × 10³ 1 0 −1 Serratia marcescens ATCC 43422 2.84 × 10³1 0 0 Enterobacter cloacae NGH 52287 2.43 × 10³ 0 −1 −1 AcinetobacterATCC 19001 2.05 × 10³ 1 1 1 Acinetobacter ATCC 27251 2.02 × 10³ 0 1 0Enterobacter aerogenes NGH 52328 1.67 × 10³ 0 0 0 Candida albicans ATCC11651 N/A 0 0 0 Candida albicans ATCC 32089 N/A 0 0 0 Candida glabrataATCC 38326 N/A 0 0 −1

Example 19 Zone of Inhibition Testing

[0252] Zone of inhibition testing was performed to demonstrate the lowmigration of silver ions from a coating containing colloidal silverchloride. This is an important factor in considering whether silver fromcould move down into the lungs. Test samples of a PVC tube were coatedwith a polymer containing 50% polyurethane/50% PVC containing colloidalsilver chloride in three concentrations: greater than 30 μg/cm²); 13μg/cm²; and 5.5 μg/cm². Using sterile scissors and forceps, test sampleswere prepared from sections ({fraction (1/4)}′ to {fraction (1/2)}″lengths) of each of the tubes. The tests were run in triplicate for eachof the following organisms:

[0253]Candida albicans, ATCC 32089 and ATCC 11651.

[0254]Enterobacter aerogenes, NGH 52328

[0255]Enterobacter cloacae, NGH 52287

[0256]Klebsiella pneumoniae, ATCC 8047 and NGH 52461-03

[0257]Pseudomonas aeruginosa, ATCC 17831 and ATCC 27318

[0258]Staphylococcus aureus NGH 52461-01

[0259] Organisms were incubated onto sample plates using known methods.Samples were then placed onto plates, each of which had been culturedwith one of the organisms. The plates were then incubated to allowgrowth of the organism.

[0260] After incubation each of the sample plates was examined forinhibition of growth of the test organism surrounding the test article.If inhibition of a test organism was noted, the distance from the edgeof the sample to the closest visible colony was measured and the zone inmillimeters (mm) was recorded. For each of the test organisms theenumeration plates (either the 1:100 dilution from the stock or the1:1000 dilution from the stock) were recorded. The approximate startingcount for each organism was recorded.

[0261] Results are as Follows.

[0262] For samples with coating at greater than 30 μg/cm²:

[0263] No zones of inhibition for any of the samples against thefollowing:

[0264]Enterobacter cloacae- NGH 52287, Enterobacter aerogenes- NGH 5232,Klebsiella pneumonia (ATCC 8047 and NGH 52461-03).

[0265] Limited zones (for 1 of the 3 samples) were observed onStaphylococcus aureus-NGH 52461-01 (a 1 mm zone), Pseudomonasaeruginosa-ATCC 17831 (a 1 mm zone), and Candida albicans-ATCC 11651 (a2 mm zone).

[0266] Zones were observed on all three samples for Candidaalbicans-ATCC 32089 (2-3 mm zones) and Pseudomonas aeruginosa-ATCC 27318(1 mm zones).

[0267] For samples with coating at 13 μg/cm²:

[0268] No zones of inhibition for any of the samples against thefollowing: Pseudomonas aeruginosa-ATCC 17831, Enterobacter cloacae-NGH52287, Enterobacter aerogenes-NGH 52328 and Klebsiella pneumonia (ATCC8047 and NGH 52461-03).

[0269] Limited zones (for 1 of the 3 samples) were observed forStaphylococcus aureus-NGH 52461-01 (1 mm zone) and Candida albicans-ATCC11651 (1 mm zone).

[0270] Zones were observed for 2 of the 3 samples for Candidaalbicans-ATCC 32089 (1 mm zones) and Pseudomonas aeruginosa-ATCC 27318(1 mm zones).

[0271] For samples with coating at 5.5 μg/cm²:

[0272] No zones of inhibition for all three samples against thefollowing: Candida albicans-ATCC 11651, Candida albicans-ATCC 32089,Enterobacter cloacae-NGH 52287, Enterobacter aerogenes-NGH 52328,Klebsiella pneumoniae-ATCC 8047, Klebsiella pneumoniae-NGH 52461-03,Pseudomonas aeruginosa-ATCC 17831 and Staphylococcus aureus-NGH52461-01.

[0273] Zones of 1 mm were observed on all three samples of Pseudomonasaeruginosa-ATCC 27318.

Example 20 Elution Testing and Microbial Adherence Testing After ElutionTesting

[0274] Elution profile testing was conducted on ETTs to simulate andevaluate the release of the silver when exposed to body fluids. Theincubation solution was 0.90% saline solution. Cuffed tracheal tubesmade of PVC and having a diameter of 7.5 mm were obtained. The tubeswere coated with a polymer coat in which the polymer was 50% PVC and 50%polyurethane. The coating also contained 5% colloidal silver chlorideprepared by combining silver nitrate and sodium chloride (using theprocedures of Example 25). Sterile coated tubes were cut into 1.0 cmpieces starting about 1 cm from edge of where the cuff is adhered. TheET tube pieces were separated as they were cut for assay of totalsilver, bacterial adherence after elution, and assay for total silverafter elution. All total silver analyses (also referred to as “silverassays” “total silver assays”) in this Example and anywhere else in thisapplication involved verified assay methods.

[0275] Samples of coated tubes for total silver assay after elution andbacterial adherence after elution were placed into pre-heated vials (3pieces per vial) containing the incubation solution and incubated for 1hour at 37° C. in an oven. Pieces were then removed from the vials,drained on the inner vial walls, placed in a second set of vials, eachcontaining 30 ml incubation solution, and incubated for another hour at37° C., for a cumulative incubation time of 2 hours. Pieces were thenremoved from the vials, drained on the inner vial walls, placed in athird set of labeled, pre-heated vials containing 30 ml of theincubation solution, and incubated for 2 more hours at 37° C., for acumulative incubation time of 4 hours. Pieces were then removed, drainedon the inner vial walls, placed in a fourth set of labeled, pre-heatedvials containing 30 ml incubation solution and incubated for 4 morehours in an oven at 37° C., for a cumulative incubation time of 8 hours.Pieces were then removed from the fourth set of vials, drained on theinner vial walls, placed in a fifth set of labeled, pre-heated vialscontaining 30 ml incubation solution, and incubated for 16 more hours inan oven at 37° C., for a cumulative incubation time of 24 hours.

[0276] At the conclusion of 24 hours, three samples were removed andsubjected to total silver analysis. At the same time, six samples wereremoved, dried, sterilized with ethylene oxide, and subjected tobacterial adherence testing using Pseudomonas aeruginosa pursuant to theprocedures in Example 18 above. All other samples were removed from thevials, drained on the inner vial walls, placed in another set of vials,each containing 30 ml incubation solution, and incubated for another 48hours (two days) at 37° C., changing incubation solution daily, for acumulative incubation time of three days.

[0277] At the conclusion of three days, three samples were removed andsubjected to total silver analysis. At the same time, six samples wereremoved, dried, sterilized with ethylene oxide, and subjected tobacterial adherence testing using Pseudomonas aeruginosa pursuant to theprocedures in Example 18 above. All other samples were removed from thevials, drained on the inner vial walls, placed in another set of vials,each containing 30 ml incubation solution, and incubated for another 96hours (four days) at 37° C., changing incubation solution daily, for acumulative incubation time of seven days.

[0278] At the conclusion of seven days, three samples were removed andsubjected to total silver analysis. At the same time, six samples wereremoved, dried, sterilized with ethylene oxide and subjected tobacterial adherence testing using Pseudomonas aeruginosa pursuant to theprocedures in Example 18 above. All other samples were removed from thevials, drained on the inner vial walls, placed in another set of vials,each containing 30 ml incubation solution, and incubated for another 168hours (7 days) at 37° C., changing incubation solution daily, for acumulative incubation time of 14 days.

[0279] At the conclusion of 14 days, three samples were removed andsubjected to total silver analysis. At the same time, six samples wereremoved, dried, sterilized with ethylene oxide, and subjected tobacterial adherence testing using Pseudomonas aeruginosa pursuant to theprocedures in Example 18 above. All other samples were removed from thevials, drained on the inner vial walls, placed in another set of vials,each containing 30 ml incubation solution, and incubated for another 168hours (7 days) at 37° C., changing incubation solution daily, for acumulative incubation time of 21 days.

[0280] At the conclusion of 21 days, three samples were removed andsubjected to total silver analysis. At the same time, the six remainingsamples were removed, dried, sterilized with ethylene oxide, andsubjected to bacterial adherence testing using Pseudomonas aeruginosapursuant to the procedures in Example 18 above.

[0281] Samples that were not eluted were also assayed using total silveranalysis. These non-eluted samples provided the initial (pre-elution)silver concentration values for each tube.

[0282] Total Silver Analysis results were used to calculate silver lossfor each tube at each interval. The percent loss of silver wascalculated by dividing the concentration of silver remaining on thesoaked pieces by the initial silver concentration and multiplying theresult by 100. Results are presented in Table 7. TABLE 7 % Silver Lossand Supporting Data Time Conc. (ug/cm²) After Soak. (ug/cm²) % Loss 24hours 12.61 7.79 38.23  3 days 13.42 5.33 60.31  7 days 14.21 2.19 84.5714 days 14.47 3.71 74.40 21 days 13.28 2.63 80.20

[0283] The saline elution model indicates that after 14 daysapproximately 25% of the silver remains.

[0284] Uncoated tubes were then prepared for comparison of microbialadherence by subjecting them to the same elution procedures as for thetest samples

[0285] Results of the bacterial adherence testing after saline elutionof the samples for 1, 3, 7, 14, and 21 days are shown in Table 8 andappear in the graph set forth in FIG. 5. TABLE 8 Mean CFU/mm² Standarddeviation Day Uncoated Coated Uncoated Coated 1 5.78E+04 7.27E+033.29E+03 5.57E+02 3 3.53E+04 6.66E+03 8.41E+03 9.33E+02 7 3.00E+041.28E+04 2.07E+03 1.26E+03 14 6.80E+04 1.12E+04 9.48E+03 6.09E+03 216.26E+03 1.12E+04 1.02E+03 1.32E+03

[0286] All saline-eluted coated samples were found to have bettermicrobial adherence performance, i.e., reduced microbial adherence interms of CFU/mm², as compared to uncoated controls for up to 14 days ofelution.

Example 21 Coefficient of Friction Testing

[0287] Sixty (60) coated and sixty uncoated samples of each type anddiameter tube were used in this testing and testing was conducted inpairs, resulting in 30 data points per tube size. Substrate tubes werePVC. For coated tubes, the coating was a polymer solutions in which thepolymers were 50% PVC and 50% polyurethane. The coating also containedsilver in a concentration of 5%, present as colloidal silver chloride.Coefficient of friction (COF) was determined by measuring the forceneeded to draw an object resting on a pair of tubes along a portion ofthe length of those two tubes. In each test, a pair of identical samplespreviously hydrated in water at 37° C. for 1 hour, 1 day, 7 days, 14days or 21 days, was placed in a trough of 37° C. water. A stainlesssteel sled weighing 390 grams and having a flat bottom surface andhorizontal dimensions of 2.5 inches by 2.5 inches was wrapped with acellulose membrane (dialysis tubing, Spectrapor #1, Spectrum MedicalIndustries, Inc.). The sled was then pulled mechanically in alongitudinal direction along the surfaces of the pairs of samples for adistance of approximately 5 inches at a constant rate of 6inches/minute. The force required to pull the sled at this rate wasrecorded continuously and averaged over the test period the sled waspulled. Force measurements used a Chatillon Model DGGHS force gauge.Pull force data points were measured in grams and divided by the weightof the sled to generate a unitless coefficient of friction number. TheCOF numbers are averaged to give an average COF value for the thirtydata points. Results for the uncoated (U/C) and coated (C) tubes arepresent in Table 9. TABLE 9 COEFFICIENT OF FRICTION DATA Type 1 hr. 1day 7 days 14 days 21 days 6.0 mm inner diameter tubes U/C 0.277 ± 0.1250.292 ± 0.034 0.414 ± 0.079 0.430 ± 0.074 0.297 ± 0.047 C 0.360 ± 0.0310.347 ± 0.035 0.298 ± 0.032 0.292 ± 0.030 0.246 ± 0.025 7.5 mm innerdiameter tubes U/C 0.342 ± 0.060 0.350 ± 0.065 0.347 ± 0.054 0.315 ±0.066 0.328 ± 0.057 C 0.337 ± 0.042 0.336 ± 0.034 0.262 ± 0.033 0.226 ±0.037 0.231 ± 0.035 10.0 mm inner diameter tubes U/C 0.332 ± 0.076 0.318± 0.059 0.317 ± 0.059 0.272 ± 0.069 0.299 ± 0.063 C 0.373 ± 0.037 0.269± 0.031 0.200 ± 0.023 0.161 ± 0.030 0.138 ± 0.039

Example 22

[0288] Samples containing different concentrations of silver salts inthe coatings were prepared to evaluate the effect of differentconcentrations of silver salts in the coating used on endotracheal (ET)tubes. PVC endotracheal tubes were coated with a polymer coating inwhich 50% of the polymer was PVC and 50% was polyurethane. The coatingswere prepared with colloidal silver chloride by adding silver nitrateand sodium chloride. Coatings were prepared containing 1%, 2.5%, 5%,10%, and 15% silver by dry coating weight. Uncoated samples and sampleswith coatings containing each of these silver concentrations were testedfor coefficient of friction (COF) using the procedures of Example 21,above; zone of inhibition, using the procedures of Example 19, above;and microbial adherence using the procedures of Example 18, above. TotalSilver Analysis was also performed using validated methods.

[0289] COF Results

[0290] Testing was performed on endotracheal tubes from each dosageconcentration after a 1 hr, 1 day, 7 day, 14 day, and 21 day soak inheated water. Results are presented in Table 10. TABLE 10 Coefficient ofFriction for Different Concentrations After Soaking for DifferentPeriods of Time CONC 1 hr. 1 day 7 days 14 days 21 days   1% 0.140 ±0.020 0.133 ± 0.023 0.095 ± 0.004 0.104 ± 0.008 0.101 ± 0.012 2.5% 0.215± 0.023 0.229 ± 0.022 0.152 ± 0.031 0.105 ± 0.016 0.107 ± 0.012   5%0.357 ± 0.051 0.368 ± 0.036 0.254 ± 0.026 0.172 ± 0.050 0.116 ± 0.023 10% 0.373 ± 0.030 0.354 ± 0.019 0.230 ± 0.025 0.230 ± 0.020 0.229 ±0.034  15% 0.371 ± 0.026 0.380 ± 0.025 0.276 ± 0.017 0.309 ± 0.048 0.224± 0.016

[0291] Zone of Inhibition Results:

[0292] The 1% concentration produced no zone of inhibitions against thefollowing: Pseudomonas aeruginosa, Staphylococcus aureus, and Candidaalbicans.

[0293] The 2.5% concentration produced no zone of inhibitions againstthe following: Pseudomonas aeruginosa, Staphylococcus aureus, andCandida tropicalis.

[0294] The 5% concentration produced no zone of inhibitions against thefollowing: Pseudomonas aeruginosa, and Staphylococcus aureus. Candidatropicalis produced a zone on one of three samples but was measured tobe less than 1 mm.

[0295] The 10% concentration produced no zone of inhibitions against thefollowing: Pseudomonas aeruginosa, Staphylococcus aureus, and Candidaalbicans.

[0296] The 15% concentration produced no zone of inhibitions against thefollowing: Pseudomonas aeruginosa, and Staphylococcus aureus. Candidatropicalis produced a zone on two of three samples.

[0297] Bacterial Adherence Results:

[0298] Results in DPM and (except Candida) in CFU/MM² are presented inTables 11 through 15. All controls (referred to as “CONT” in the tablesbelow) were uncoated silicone. Coated tubes are provided as “ET TUBE.”TABLE 11 Bacterial Adherence Data Staphylococcus aureus ATCC 700698CFU/mm² CONT ET TUBE 1.0% S 2.5% S 1 2.65E+04 4.27E+04 1.24E+04 1.27E+042 3.43E+04 3.84E+04 1.33E+04 1.14E+04 3 2.97E+04 3.87E+04 1.11E+041.28E+04 4 3.42E+04 3.72E+04 1.42E+04 1.16E+04 5 3.10E+04 4.36E+041.21E+04 ?? AVG 3.11E+04 4.01E+04 1.26E+04 1.22E+04 s.d. 3.28E+032.83E+03 1.20E+03 7.22E+02

[0299] TABLE 12 Bacterial Adherence Data Pseudomonas aeruginosa ATCC17831 CFU/mm² CONT ET TUBE 1.0% S 2.5% S 1 3.55E+04 5.79E+04 1.00E+049.09E+03 2 4.42E+04 6.27E+04 9.14E+03 8.85E+03 3 3.93E+04 7.16E+049.59E+03 9.05E+03 4 4.03E+04 8.52E+04 8.62E+03 1.21E+04 5 3.93E+047.87E+04 9.30E+03 7.67E+03 AVERAGE 3.97E+04 7.12E+04 9.33E+03 9.35E+03s.d. 3.11E+03 1.12E+04 5.15E+02 1.65E+03

[0300] TABLE 13 Adherence Data C. albicans ATCC 11651 DPM CONT ET TUBE2.5% S 5% S 10% S 15% S #1 184381 640012 26935 36675 26708 24970 #2116794 512099 35359 24761 26694 16840 #3 174946 273695 28715 11643 2608421918 #4 200527 618035 22848 23747 26018 22977 #5 107633 273231 2857623195 16054 22027 Background 55 46 55 51 54 53 Surface 428 560 560 560560 560 Area (mm²) #1 430.668 1142.796 48 65.4 47.596 44.495 #2 272.755914.380 63.043 44.125 47.571 29.977 #3 408.624 488.659 51.179 20.746.482 39.045 #4 468.393 1103.552 40.702 42.314 46.364 40.936 #5 251.350487.830 50.930 41.329 28.571 39.239 Average 366.358 827.444 50.77142.774 43.317 38.738 s.d. 97.879 321.463 8.060 15.838 8.264 5.36

[0301] TABLE 14 Bacterial Adherence Data Staphylococcus aureus ATCC700698 CFU/mm² CONT ET TUBE 2.5% S 5% S 10% S 15% S 1 1.05E+04 2.64E+049.13E+03 1.17E+04 1.21E+04 1.57E+04 2 2.35E+04 2.65E+04 9.81E+031.15E+04 1.11E+04 1.24E+04 3 1.42E+04 2.52E+04 1.02E+04 1.31E+041.60E+04 1.32E+04 4 1.38E+04 2.76E+04 9.86E+03 1.12E+04 1.64E+041.47E−04 5 1.71E+04 2.27E+04 1.21E+04 1.27E+04 1.28E+04 1.26E+04 AVG1.58E+04 2.57E+04 1.02E+04 1.20E+04 1.37E+04 1.37E+04 s.d. 4.92E+031.86E+03 1.14E+03 8.21E+02 2.36E+03 1.44E+03

[0302] TABLE 15 Bacterial Adherence Data Pseudomonas aeruginosa ATCC17831 CFU/mm² CONT ET TUBE 2.5% S 5% S 10% S 15% S 1 4.62E+04 1.04E+058.96E+03 8.89E+03 9.01E+03 5.57E+03 2 5.86E+04 1.09E+05 8.30E+038.47E+03 1.17E+04 8.19E+03 3 4.69E+04 1.12E+05 1.15E+04 8.38E+039.27E+03 7.90E+03 4 4.45E+04 1.18E+05 8.01E+03 8.10E+03 9.06E+036.55E+03 5 4.68E+04 1.07E+05 9.39E+03 1.12E+04 8.15E+03 1.59E+04 AVG4.86E+04 1.10E+05 9.23E+03 9.01E+03 9.44E+03 8.81E+03 s.d. 5.67E+035.09E+03 1.38E+03 1.27E+03 1.33E+03 4.07E+03

[0303] Summary:

[0304] All concentrations tested were found to have reduced bacterialadherence against Pseudomonas aeruginosa when compared to a PVC controltube.

[0305] All concentrations tested were found to have reduced bacterialadherence against Staphylococcus aureus when compared to a PVC controltube.

[0306] All concentrations tested were found to have reduced bacterialadherence against Candida albicans when compared to a PVC control tube.

[0307] Total Silver Analysis results. The results (from on five samplesfor each concentration) are presented in Table 16. TABLE 16 Average %Silver Silver measured in μg/cm² μg/cm² (n = 5)   1% 2.01, 1.95, 2.00,1.80, 2.18 1.99 2.5% 5.37, 5.61, 5.42, 5.69, 5.92 5.60   5% 12.81,13.10, 11.85, 12.81, 12.87 12.69  10% 29.95, 27.89, 28.13, 29.41, 28.7428.82  15% 44.80, 44.45, 49.89, 42.75, 48.08 46.00

Example 23 Exposure to Drugs and Chemicals

[0308] Testing was conducted to evaluate the interaction of thesilver/hydrogel coating with various chemicals to which the device couldbe expected to come into contact during normal use.

[0309] Interaction with Nebulized Atropine Sulfate, Albuterol Sulfate,and Acetylcysteine

[0310] Separate ET tubes were exposed to one of the following drugs:Atropine Sulfate, (NDC 10019-250-20), Albuterol Sulfate, USP, 0.083%,NDC 59930-1500-6, and Acetylcysteine, USP, NDC 0074-3308-03. These aredrugs commonly used for respiratory therapy. In each case, the drugswere nebulized into a chamber containing a cuffed endotracheal tubecoated using the procedures of EXAMPLE 25, below. The nebulizer systemcomprised a compressor, reservoir hose, 5-ml-medicine cup, and a Tconnector. The T connector was joined to a 2-liter jar modified toreceive the T connector through the jar sidewall. The jar lid wasmodified to have a small port acting as a pressure relief valve. One endof the reservoir hose was connected to the hose port of a nebulizer. Thecoated tube was then placed into the 2-liter container, or chamber, andthe lid was secured. The T connector was inserted into the 2-literchamber, port located on the sidewall. 3 ml of the drug was placed intothe 5-ml.-medicine cup. The loose end of the reservoir hose was placedin the underside of the 5-ml.-medicine cup. The nebulizer was thenturned on, and run until all the drug had been nebulized. The nebulizerwas then turned off, and the samples were allowed to remain in thechamber for 30 minutes after the nebulizer had been switched off. Thetest product was removed and rinsed using deionized (DI) water bydipping sample in clean DI water twice for a total of 10 seconds.

[0311] Coefficient of friction (COF) testing was performed onendotracheal tubes from each drug exposure using the procedures setforth in Example 21 above. COF results were collected after a 1 hr, 1day, 7 day, 14 day, and 21 day soak in 37° C. water. Results arepresented in Table 17. TABLE 17 Drug 1 hr. 1 day 7 days 14 days 21 daysAcet. 0.301 ± 0.154 ± 0.097 ± 0.090 ± 0.017 0.087 ± 0.017 0.037 0.0260.002 A.S. 0.329 ± 0.192 ± 0.084 ± 0.079 ± 0.017 0.107 ± 0.030 0.0240.011 0.009 Albut 0.275 ± 0.228 ± 0.076 ± 0.086 ± 0.016 0.108 ± 0.0110.027 0.021 0.003

[0312] The total silver was determined using verified techniques.Results are presented in Table 18. TABLE 18 Total Silver Analysis DrugSilver Concentration (μg/cm²) n = 3 Acet. 12.92 ± 0.69 A.S. 15.01 ± 3.85Albut. 13.75 ± 0.67

[0313] Exposure to Lidocaine Jelly, Lidocaine HCl, and Lubricating Jelly

[0314] Separate ET tubes were exposed to Lidocaine Jelly, Lidocaine HCl,and Lubricating Jelly. A container was filled with enough lidocainejelly (2% lidocaine hydrochloride in a solution of water,hydroxypropylmethylcellulose, and preservatives or equivalent topicallidocaine containing formulation) such that when 3 ET tubes wereimmersed the jelly will cover the ET tubes 1 inch past the coatingtransition line. ET tubes were then immersed in the container filledwith lidocaine jelly for approximately 30 minutes. The product wasremoved after soaking and excess lubricant was allowed to drain offsurface of catheter. The product was rinsed using deionized (DI) waterby immersing sample in clean DI water bath for 5 minutes and then inanother fresh DI water bath for 1 minute. The same procedures wererepeated using lidocaine HCl (2%) in water and K-Y® lubricating jelly.

[0315] Samples were visually inspected, tested for coefficient offriction using the procedures in Example 21 above, and subjected tototal silver analysis using verified methods to determine whetherexposure to these substances adversely affected these characteristics.No coating delamination, discoloration, or other affects were observed.Coefficient of friction testing was performed on endotracheal tubes fromeach drug exposure. COF results were collected after a 1 hr, 1 day, 7day, 14 day, and 21 day soak in heated water. Results are presented inTable 19 below. TABLE 19 Drug 1 hr. 1 day 7 days 14 days 21 days Lube0.217 ± 0.164 ± 0.143 ± 0.086 ± 0.005 0.072 ± 0.004 0.021 0.023 0.022Lid. 0.327 ± 0.223 ± 0.092 ± 0.079 ± 0.004 0.084 ± 0.012 HCL 0.013 0.0210.013 Lid. 0.370 ± 0.228 ± 0.097 ± 0.088 ± 0.008 0.107 ± 0.030 Jelly0.021 0.032 0.012

[0316] Total silver analysis results are presented in Table 20 below.TABLE 20 Drug Silver Concentration (μg/cm²) n = 3 Lube 13.53 ± 3.24 Lid.HCL 14.37 ± 1.98 Lid. Jelly 14.62 ± 0.42

[0317] The ETT coating is not compromised when exposed to lubricatingjelly.

Example 24 Magnetic Resonance Imaging Interaction Testing.

[0318] Tests were conducted with coated endotracheal tubes to determinewhether magnetic resonance (MR) such as that used in magnetic resonanceimaging (MRI) would produce any effects that would be adverse to apatient in which such a tube was used. The samples included anendotracheal tube made from PVC coated with a polymer composition inwhich 50% of the polymer was PVC and 50% of the polymer waspolyurethane. The coating contained silver chloride in amounts greaterthan 30 μg/cm. MR source was a 1.5 Tesla 64 MHz MR system (Sigma MRSystem, General Electric Medical Systems, Milwaukee, Wis.).

[0319] Magnetic Field Interaction.

[0320] Translational attraction testing was conducted using a“deflection angle test,” which is described, for example, in AmericanSociety for Testing and Materials Method No. F 2052. Each individual ETtube was suspended by a 20-cm length of thin thread (weighing less than5% the weight of the ET tube) and attached to a plastic protractor sothat the angle of deflection from the vertical could be measured. Thetest was conducted at the position in the 1.5-Tesla MR system where thespatial gradient had been determined to be at a maximum in order todetermine the translational attraction with regard to an extrememagnetic field exposure condition. It was found that the highest spatialgradient for the system used for testing occurs at an off-axis positionthat is 35-cm inside the opening of the bore of the system. The magneticspatial gradient at this position was found to be 450 gauss percentimeter.

[0321] Evaluation was also performed to determine qualitatively thepresence of magnetic field-induced torque for the ET tube. A flatplastic material with a millimeter grid on the bottom was used(coefficient of friction was 0.07). Each tube was placed on the testapparatus in an orientation that was 45 degrees relative to the staticmagnetic field of the MR system. The test apparatus with ET tube wasthen positioned in the center of the MR system, where the effect oftorque from the static magnetic field was determined to be the greatestbased on a previous magnetic field survey for the MR system. Each ETtube was directly observed for any possible movement with respect toalignment or rotation relative to the static magnetic field of the MRsystem. The observation process was facilitated by having theinvestigator inside of the bore of the MR system during the testprocedure. The ET tube was then moved 45 degrees relative to itsprevious position and again observed for alignment or rotation. Thisprocess was repeated to encompass a full 360 degrees rotation ofpositions for ET tube in the MR system. The following qualitative scaleof torque was applied to the results: 0, no torque; +1, mild or lowtorque, the implant slightly changed orientation but did not align tothe magnetic field; +2, moderate torque, the implant aligned graduallyto the magnetic field; +3, strong torque, the implant showed rapid andforceful alignment to the magnetic field; +4, very strong torque, theimplant showed very rapid and very forceful alignment to the magneticfield.

[0322] Two tested samples were found to have a deflection angle of 4degrees and a qualitative torque of zero. It was thus concluded that thetubes would have relatively minor MR field interactions and that use ofthe coated tubes would create no additional risk to a patient withrespect to movement or dislodgment for the tested tube.

[0323] Heating Due to MRI

[0324] Heating due to MRI was then determined. An extreme radiofrequency(RF) power exposure experiment was performed with each ET tube placedinside of a specially-constructed, gel-filled phantom. A plastic phantomwas prepared and filled with a semi-solid gel to simulate human tissue.The gelling agent was hydroxyethyl-cellulose (HEC) in an aqueoussolution (91.48% water) along with 0.12% NaCl to create a dielectricconstant of approximately 80 and a conductivity of 0.8 S/m at 64 MHz.The phantom had dimensions and configuration to approximate the size ofthe human torso. The phantom was constructed as a torso that is a 24″high by 17″ wide rectangle with a protrusion centered in the top of thetorso to simulate a head. The protrusion was 11.5 inches high and 6.5inches wide. The torso lacked a flow to simulate blood flow and thuswould be expected to experience a more localized heating effect than inthe human body. The ET tube was fixed to a plastic frame to facilitatepositioning in the phantom and MR system during the heating experiment.The Sigma system described above was used, and the body coil served tosend and to receive RF energy.

[0325] A T1-weighted spin echo pulse sequence was used for imaging, asfollows: total imaging time, 20 minutes; axial plane; 135 msec; echotime, 20 msec; field of view, 48 cm; imaging matrix, 256×128; sectionthickness, 20.0 mm; number of section locations, 4; number ofexcitations, 27; number of echoes, 4; phasing direction, anterior toposterior; transmitter gain, 200. The pulse sequence produced a wholebody average specific absorption rate (SAR) of 1.2 W/kg and a spatialpeak SAR of 2.5 W/kg. This level of exposure exceeds that typically usedfor clinical MRI procedures.

[0326] Temperature recordings were obtained in this experiment using aLuxtron Model 3100 Fluoroptic Thermometry system previously demonstratedto be MRI-compatible and unperturbed at static magnetic field strengthsup to 9.0-Tesla (i.e. an MR spectrometer). This thermometry system hassmall fiber-optic probes (0.5 mm diameter) that respond rapidly(response time, 0.25 seconds), with an accuracy and resolution of ±0.1°C. The ET tube that underwent assessment for MRI-related heating had twothermometry probes attached to record representative temperature duringthe experiment. The probes were placed: at 0.5 mm from the end of the ETtube (Probe #1); at 0.5 mm from the center of the ET tube (Probe #2);and in the gel-phantom at a position removed (approximately 40 cm away)from the ET tube to record a reference temperature during the heatingexperiment (Probe # 3). The gel phantom with the ET tube and thermometryprobes was placed inside of the MR system. The gel-filled phantom wasallowed to equilibrate to the temperature of the environmentaltemperature for a period of one hour. The room temperature andtemperature of the bore of the MR system were 20.6° C., with a relativehumidity of 45%. The MR system fan was not on during the experiment.Baseline temperatures were recorded at 20-sec. Intervals for 5 minutes.MRI was then performed for 20 minutes with temperatures recorded at20-sec. Intervals. The highest temperature changes were +0.5° C. forProbe #1, +0.5 0° C. for Probe #2, and +0.4° C. for Probe #3.

[0327] Induced Electrical Currents

[0328] A comprehensive analysis of the interaction of the ET tube withMRI time-varying fields was performed. Measurements were made with an HPdigital multimeter using a pair of needle probes. The probes werepressed into the tubing to make good electrical contact. The followingsections of the ET tube were checked: main tube, end connector, fluerod, and inflation cuff. All sections exhibited an impedance in excessof 1 MΩ when the voltmeter probes were 1 cm apart. Thus, the ET tube isessentially an insulator when compared to conductivity of tissue. Theonly conducting section of the tube is the spring at the end of the airtube. The spring has a length of about 7 mm, a diameter of about 3 mmand has about 7 turns. The wire has a radius of about 0.1 mm. The springis covered by plastic insulating material of about 3 mm thickness. Theresistance of the spring is calculated a approximately 0.21 Ω. It wasdetermined by calculation that RF-induced temperature rise may occurnear the flanks and end of the tube that is approximately twice thebackground rise, but that this would be expected to be no more than willalready occur due to the electrical heterogeneities in the body.RF-induced heating should be otherwise imperceptible. Heating by pulsegradient current would expect to result in a temperature rise less than0.008° C.

[0329] Artifact Test

[0330] MRI artifacts were assessed for one sample of the ET tube. Thistest was accomplished by performing MR imaging with the ET tube placedinside of a gel-filled phantom. The phantom had a rectangular shape withthe following dimensions: 30-cm width, 55-cm height, 75-cm length. TheET tube was attached to a plastic frame to facilitate positioning and MRimaging within this phantom. MR imaging was conducted using the Sigmasystem described above, with a send-receive body coil.

[0331] A T1-weighted spin echo pulse sequence was used for imaging, asfollows: repetition time, 500 msec; echo time, 20 msec; field of view,30 cm; matrix size, 256×256; section thickness, 5 mm; number ofexcitations, 2; bandwidth, 16 kHz. A gradient echo (GRE) pulse sequencewas also used, repetition time, 100 msec; echo time, 15 msec; flipangle, 30 degrees; field of view, 30 cm; matrix size, 256×256; sectionthickness, 5 mm; number of excitations, 2; bandwidth, 16 kHz. Theimaging planes were oriented to encompass the long axis and short axisof the ET tube. The frequency encoding direction was parallel to theplane of imagine. The planimetry software provided with the MR systemwas used to measure the cross-sectional areas for the artifactsassociated with the ET tube. The accuracy of this planimetry method is±10.

[0332] The artifacts that appeared on the MR images were shown aslocalized signal voids (i.e. signal loss) easily recognized on images.In general, the GRE pulse sequence produced larger artifacts that theT1-weighted, spin echo pulse sequence for the ET tube. It was concludedthat the artifacts should not affect the function of MR systems unlessthe imaging area of interest is in the exact same position or close tothe device. Results appear below in Table 21. TABLE 21 Summary of MRIArtifact Information for ET Tube Signal Void 2,406 mm² 161 mm² 2,598 mm²184 mm² Size Static Magnetic 1.5 1.5 1.5 1.5 Field (T) Pulse SequenceT1-SE T1-SE GRE GRE TR (sec.) 500 500 100 100 TE (sec.) 20 20 15 15 FlipAngle N/A N/A 30° 30° Bandwidth 16 kHz 16 kHz 16 kHz 16 kHz Field ofView 30 cm 30 cm 30 cm 30 cm Matrix Size 256 × 256 256 × 256 256 × 256256 × 256 Section 5 mm 5 mm 5 mm 5 mm Thickness Maximum 6.3 mT/m 6.3mT/m 6.3 mT/m 6.3 mT/m Readout Gradient Strength Imaging Plane parallelperpendicular parallel perpen- dicular Phantom Filler gel gel gel gel

Example 25

[0333] A coating composition for PVC catheters was prepared as follows:a 3.2% solution of a polyether polyurethane-urea block copolymeravailable from CardioTech International, Inc. was prepared in a mixtureof THF/alcohol in a 75/25 ratio by weight. A 4.0% solution of Polyvinylchloride (PVC) was then prepared in THF. The two solutions were thencombined in amounts that provide a 50/50 ratio by weight of the twopolymers in solution. A sufficient quantity of 10% silver nitrate(AgNO₃) solution in water was then added to the polyurethane-urea/PVCpolymer solution to produce a final silver concentration ofapproximately 5%, based on coating solids in the solution. A 2% sodiumchloride solution in water was added to the coating solution in anamount sufficient to react with 100% of the AgNO₃ to produce a colloidof the poorly water soluble salt AgCl from all of the AgNO₃. The NaClsolution was added slowly to the polymer solution with stirring, and thesolution began to turn cloudy with the formation of the fine colloidalAgCl. The amount of water in the final coating solution was about 4.8%of the total solvent weight. The amount of alcohol in the solution wasabout 13.3% of the total solvent weight. A PVC endotracheal tube wasthen coated by dipping it into the coating composition, followed bydrying using standard methods. The tube was dipped to within about 4 cmfrom the end that resides outside the patient. The finished coatingcontained only the poorly water soluble, and therefore slow releasing,AgCl to provide primarily surface antimicrobial activity and limit theamount of silver released that could find its way into the lungs.

[0334] Finally, it will be understood that the preferred embodimentshave been disclosed by way of example, and that other modifications mayoccur to those skilled in the art without departing from the scope andspirit of the appended claims.

What is claimed is:
 1. A composition comprising: at least one polymer;and a colloid comprising a salt or oxide of one or more oligodynamicmetals; wherein the salt or oxide of one or more oligodynamic metalsinhibits microbial adherence of one or more organisms to thecomposition.
 2. The composition of claim 1 wherein the salt or oxide ofone or more oligodynamic metals creates a zone of inhibition to the oneor more pathogens when placed on a culture of the one or more pathogens.3. The composition of claim 1 wherein the salt or oxide of one or moreoligodynamic metals does not create a zone of inhibition to the one ormore pathogens when placed on a culture of the one or more pathogens. 4.The composition of claim 1 wherein the salt or oxide of one or moreoligodynamic metals is a silver salt.
 5. The composition of claim 1wherein the silver salt is selected from silver chloride, silver iodide,silver citrate, silver lactate, silver acetate, silver propionate,silver salicylate, silver bromide, silver ascorbate, silver laurelsulfate, silver phosphate, silver sulfate, silver oxide, silverbenzoate, silver carbonate, silver sulfadiazine, and silver gluconate.6. The composition of claim 1 wherein the colloid comprises the salt ofmore than one oligodynamic metal.
 7. The composition of claim 1 whereinthe one or more oligodynamic metal salts comprise salts having differentsolubilities in water.
 8. The composition of claim 1 wherein the atleast one polymer is selected from polyurethanes, polyvinylpyrrolidones,polyvinyl alcohols, polyethylene glycols, polypropylene glycols,polyoxyethylenes, polyacrylic acid, polyacrylamide, carboxymethylcellulose, dextrans, polysaccharides, starches, guar, xantham and othergums, collagen, gelatins, biological polymers, polytetrafluoroethylene,polyvinyl chloride, polyvinylacetate, poly(ethylene terephthalate),silicone, polyesters, polyamides, polyureas, styrene-block copolymers,polymethyl methacrylate, polyacrylates, acrylic-butadiene-styrenecopolymers, polyethylene, polystyrene, polypropylene, natural andsynthetic rubbers, acrylonitrile rubber, cellulose, and mixtures,derivatives, and copolymers thereof.
 9. The composition of claim 1wherein the silver salt is silver chloride and the composition containssilver chloride present in an amount between about four and about sixpercent based on the total weight of solids in the composition.
 10. Anarticle comprising the composition of claim
 1. 11. The article of claim10, wherein the article comprises a substrate material and a coating onat least part of one or more surfaces of the substrate material and thecoating comprises the composition.
 12. The article of claim 11 whereinthe coating covers part of at least one surface of the substrate anddoes not cover another part of the surface.
 13. The article of claim 12wherein the part of the surface that is not covered is sufficientlytransparent to allow visual inspection of the interior of the article.14. The article of claim 11 wherein the coating comprises multiplecoating layers.
 15. The article of claim 10 wherein the articlecomprises a medical device.
 16. The article of claim 10 wherein the oneor more salt or oxides of oligodynamic metals are present in aconcentration of between about 10 and about 15 micrograms per squarecentimeter of surface area of the articles.
 17. A method for themanufacture of an article comprising the steps of (1) forming asolution, dispersion, or combination thereof comprising the compositionof claim 1; and (2) drying the solution to create a solid polymericarticle.
 18. A method for the manufacture of an article comprising thesteps of: (1) forming the composition of claim 1; (2) drying thecomposition; and (3) processing the composition with the application ofheat to form the article.
 19. A method for the manufacture of an articlecomprising the steps of (1) forming the composition of claim 1; (2)compounding the composition formed in (1) with one or more polymers; and(3) processing the composition formed in (2) with the application ofheat to form the article.
 20. A method for the manufacture of an articlecomprising dipping a form in the composition of claim
 1. 21. A methodfor the manufacture of an article comprising casting the composition ofclaim 1 into a preselected shape.
 20. A method for delivery of one ormore oligodynamic metals, salts of oligodynamic metals, oxides ofoligodynamic metals, or combinations thereof to a desired locationcomprising: providing the composition of claim 1, and implanting,administering, inserting, or otherwise placing the composition underconditions effective to deliver oligodynamic metals, salts ofoligodynamic metals, oxides of oligodynamic metals, or combinationsthereof, to the desired location.
 21. A method of treatment of a cell,tissue, or organism, comprising implanting, administering, inserting, orotherwise placing the composition of claim 1 under conditions effectiveto deliver one or more oligodynamic metals, salts of oligodynamicmetals, oxides of oligodynamic metals, or combinations thereof to thecell, tissue, organism, or a portion of the cell, tissue, or organism.22. The use of the composition of claim 1 in the preparation of anarticle or medicament for delivery of one or more oligodynamic metals,salts of oligodynamic metals, oxides of oligodynamic metals, orcombinations thereof to the cell, tissue, organism, or a portion of thecell, tissue, or organism.